Prof. Dr. Markus Meuwly Department of Chemistry Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 8 foundShow per page10 10 20 50 Intermolecular Interactions and the Role of Dynamics for Chemical Reactions in Complex Systems Research Project | 1 Project MembersThe goal of this project is to develop, implement and applycomputational strategies to characterize, understand and predictproperties of complex systems at a molecular level. To this end,computational techniques including multipolar (MTP) force fields,adiabatic reactive molecular dynamics (ARMD) simulations, andmolecular mechanics with proton transfer (MMPT) are used and furtherdeveloped. Multipolar force fields will be extended to routinespectroscopic applications such as 1- and 2-dimensional infraredspectroscopies. This will be applied to spectroscopic probes,primarily nitriles (-CN), which are sensitive environmental probes forprotein interiors. Fluctuating MTPs will be used to study the 1d- and2d-IR spectroscopy of-CN-containing inhibitors in human aldosereductase (hALR2) and benzonitrile in Lysozyme. Multiplesurface-ARMD will be combined with the fewest switching surfacehopping (FSSH) methodology for investigating nonadiabatic effects inchemical dynamics. This will considerably extend the range ofapplicability for MS-ARMD. Initial applications concernphotodissociation and recombination of ICN in solution and O2formation in amorphous ice at low temperatures. In a next step, thestructural and solvent dynamics upon oxidation from Cu(I) to Cu(II) incopper-phenanthroline complexes will be investigated. Also, standardARMD simulations will be used to study multiple-ligand dynamics in theactive site of truncated Hemoglobin N which is responsible fordenitrification. Molecular mechanics with proton transfer will becombined with multi state-ARMD to investigate proton transfer in thecondensed phase on extended time scales. Computationally efficientevaluation of accurate energy functions is particularly important whenusing it for multidimensional spectroscopy which typically requiresextensive conformational sampling to converge the frequency frequencycorrelation function. The developments will allow atomisticallyrefined simulations of the recently recorded 2d-IR spectrum of theexcess proton in liquid water. The present proposal involves tworesearch themes: reactive simulations in the condensed phase andcomputational vibrational spectroscopy which both require accuraterepresentations of the intermolecular interactions. International Research Training Group IRTG 1038 "Catalysts and Catylytic Reactions for Organic Synthesis. Research Project | 5 Project MembersUnder the roof of the International Research Training Group "Catalysts and Catalytic Reactions for Organic Synthesis" (IRTG 1038) six research groups from the Faculty of Chemistry, Pharmacy and Earth Sciences of the University of Freiburg i. Br. and five research groups from the Department of Chemistry of the University of Basel will combine their research and teaching activities in the field of catalysts and catalytic reactions for organic synthesis. Intensive bilateral collaboration will be ensured by the formation of joint research projects. The scientific research program encompasses all important areas of catalytic organic synthesis, such as catalyst development including combinatorial methods employing self-assembly catalysts, peptide-based organocatalysts and mass spectrometric catalyst screening, enzyme catalysis, catalytic reaction cascade development, asymmetric catalysts based on DNA templates, position-selective cross-coupling of multifunctional building blocks, and application to total synthesis of biologically relevant target molecules. Furthermore, theoretical and experimental methods will be implemented in order to get a deeper understanding of new catalyst systems and the mechanism of catalytic reactions. The International Research Training Group will provide the students with a vibrant research atmosphere and with a qualification program to develop a thorough knowledge of catalysts and catalytic reactions and their application to organic synthesis. The incorporation of industrial experts in the qualification program will ensure practical relevance and will demonstrate the importance of catalysts and catalytic reactions in the chemical and pharmaceutical industry. Optimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology:Theoretical and Practical Aspects Research Project | 3 Project MembersOptimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology: Theoretical and Practical Aspects In the past three decades, homogeneous and enzymatic catalysis have evolved independently to provide the necessary tools for the synthesis of high value added products. These two approaches are complementary in many respects. With the aim of exploiting the advantages of both fields, artificial metalloenzymes have recently attracted increasing attention. Such hybrid catalysts result from combining an organometallic moiety, typical of homogeneous catalysts, with a protein, reminiscent of an enzyme. Following this approach, several artificial metalloenzymes have been designed, optimized and structurally characterized. Within this project, it is proposed to combining both in-silico (computer-based) and in-vitro (experiment) screening of artificial metalloenzymes. For this purpose, mixed quantum mechanical/classical mechanics (QM/MM) calculations of artificial ketoreductases based on the biotin-avidin technology will be carried out. Because QM/MM is computationally a very demanding technique, also force field-based approaches will be further developed. One of them - VALBOND-TRANS - is specifically designed for treating metal centers in particular bonding topologies. Until now, VT has only been parametrized for octahedral complexes and we seek to extend this to square planar compounds. Finally, the insight obtained from the computational studies will be applied towards the chemogenetic optimization of artificial keto-reductases This project aims at providing alternative catalytic solutions with potentially broad (industrial) applications. Artifical enzymes have the potential to combine some of the attractive features of both homogeneous and enzymatic catalysis. Here we try to pursue a targeted approach that is inspired by how nature addresses such problems and that is guided by reliable computations. Weakly Coordinatting Anions and Bidentate Lewis Acids - New Possibilities in Catalysis. Research Project | 3 Project MembersToday's world is unthinkable without catalysis and efficient catalysts. Although the focus of Organic Chemistry is truly on carbon, catalysis involves in nearly all cases other elements, especially transition metals. In this research project, which is part of the International Research Training Group IRTG 1038 "Catalysis and Catalytic Reactions for Organic Synthesis", we want to investigate two kinds of catalytic processes. The first one deals with the influence of weakly coordinating anions (WCAs) on transition metal, especially gold catalyzed reactions, and the second one is the use of bidentate Lewis acids as catalysts in organic synthesis. Due to constrains in resources only the second part can be realized. The multidisciplinary nature of the problems, ranging from organic synthesis and inorganic chemistry to molecular interactions between complex solvent, catalyst and substrate is re-flected in a joint effort by two groups from the University of Basel, Dr. Hermann Wegner (or-ganic synthesis and catalysis) and Prof. Markus Meuwly (computational and theoretical chem-istry), and one group from the University of Freiburg, Prof. Ingo Krossing (inorganic chemistry). Bidentate Lewis acids have hardly applied as catalysts in organic synthesis up to now. Here, a first proof of principle has been shown in the Wegner group for an Inverse Electron Demanding Diels-Alder (IEDDA) reaction of 1,2-diazene to 1,2-substituted aryl compounds. Using spectroscopic as well as computational tools should clarify the exact mechanism, influences and other parameter on the reaction. By this approach we will shine light on this interesting class of unexplored catalysts and open up the way for optimizing the IEDDA to a general applicable method for the preparation of 1,2-substituted arenes. With a detailed picture of the transformation the knowledge will be used to find other application for bidentate Lewis acids in catalysis, e.g. other challenging cycloaddition reactions or aldol type chemistry. Insights into bidentate Lewis acids as catalysts in organic synthesis will be a benefit for the whole community and stimulate the development greatly in this area. The multidisciplinary approach offers the enormous advantage to tackle the problem from various dimensions. As this research project is part of a ProDoc program it has the great advantage to give the par-ticipating students a deep insight into various disciplines and how to combine them to address questions in catalysis. Computational Analytical Chemistry: Research Project | 1 Project MembersThe goal of the project is to develop quantitative numerical methods and computational strategies to understand the physico-chemical properties of reversed phase liquid chromatography that lead to selectivity and retention. Based on our initial investigation and characterization of a realistic chromatographic system the influence of different functionalizations of the stationary phase will be investigated to provide further information about the selectivity of alkyl columns. In a next step, based on the detailed atomistic simulations which have already been carried out in our group and which have been validated in view of experimental results, more efficient representations of the intermolecular interactions are developed and used in coarse grained molecular dynamics simulations. Describing electrostatic interactions with distributed multipoles of higher order (up to hexadecapole) has been shown in our group to lead to a quantitative understanding of the energetics and dynamics in condensed-phase simulations. Such extensions and generalizations will also be pursued for the coarse grained simulations. Reversed Phase Liquid Chromatography (RPLC) is a widely used analytical technique in pharmaceutical separations, the food industry, in life-science applications (peptide and protein separation), and in the analysis of industrial polymers. Despite this importance (up to 90 % of all analytical separations on low molecular weight samples use RPLC) the molecular mechanisms for retention and selectivity are still unclear. Important questions concern, for example, the understanding of solute-solvent interactions, the influence of varying acidities of the solvent and the role of the stationary phase in creating a microheterogeneous environment and ultimately to unravel the origin of selectivity of columns with different functionalizations and solvent compositions. Such questions are ideally suited to be pursued with computer simulations which are also validated in view of experimental data. Atomistic Modelling and Experimental Validation of Enzyme-Inhibitor Interactions of Dengue Fever Virus Methyltransferase: Towards new approaches to target neglected tropical diseases. Research Project | 4 Project MembersDengue fever is a viral infectious disease that is prevalent in tropical regions. It is transmitted by mosquitoes and annually affects 50 to 100 million people worldwide. No vaccinations or specific drug treatments are available. Several of the virus' proteins are essential for its pathogenicity and are required by the virus to reproduce in host cells. In cases where three-dimensional structural models of the binding site of the proteins are known, computer simulations (i.e. virtual screening or molecular docking) can be used to simulate possible interaction between these proteins and small inhibitor molecules with the potential to become drug candidates. However, current algorithms used in virtual screening must make a number of approximations in order to be able to screen a large number of compounds within reasonable time. In contrast, atomistic simulations based on the physicochemical properties of molecules using Newton's laws of motion to determine the strength of binding between ligand and receptor molecules can provide more accurate, but computationally more demanding, predictions of the affinity with which a molecule binds to specific site in a protein. In this study, we focus our computational work on simulating the binding of small-molecule inhibitors to the viral enzyme NS5 methyltransferase. In a first step, a library of commercially available chemical compounds is searched by virtual screening for molecules likely to bind to the viral enzyme. Chemical compounds emerging from this study as possible inhibitors of dengue methyltransferase will be tested in biochemical and biological assays for their ability to inhibit viral replication in cultured cells. For this point, we are closely collaborating with the Novartis Institute for Tropical Diseases in Singapore. The results of the experimental measurements will in return increase our understanding of the physicochemical interactions governing methyltransferase inhibitor interactions and allow us to improve the accuracy of our molecular modeling simulations by calibrating interaction parameters with experimental binding affinities. Despite the clinical interest in MTase as drug target, little is known about the enzymatic mechanism of the methyl transfer reaction of this class of methyl transferases. In the second phase of the project, we have therefore focused on detailed molecular dynamics simulations of the transfer reaction. We moreover hope that this research will contribute to the discovery of new lead compounds against neglected tropical diseases, leading to the development of drugs that are offered at cost in the affected countries. Intermolecular Interactions and the Role Research Project | 1 Project MembersThe goal of the project is to develop numerical methods and computational strategies to understand the energetics and dynamics of chemical reactions in complex environments and to apply them to chemically and biologically interesting systems. Using a combination of reactive molecular dynamics (RMD), improved force fields, potential energy surface ``morphing'' procedures, and electronic structure calculations, reactions including hydrogen/proton-transfer, ligand-binding and electron-coupled proton transfer are investigated at a quantitative level. The reactive molecular dynamics method, which was developed for rebinding reactions of diatomic ligands to myoglobin, I) will be generalized to treat enzymatic and rebinding reactions between arbitrary ligands and substrates and II) will be extended to electron-transfer reactions. Specific applications of reactive molecular dynamics include ligand binding in myoglobin, Cytochrome P450, and Azotobacter Vinelandii Ferredoxin I (FdI). These are systems for which detailed experimental data and information from previous simulations is available. More reliable intermolecular interaction potentials will be derived by ``morphing'' suitable zeroth-order potential energy surfaces. This strategy will be applied to problems from molecular spectroscopy to proton transfer in proteins (e.g. FdI). To improve the description of the electrostatic interaction between ligands and the surrounding protein in ligand-binding studies we currently develop and implement a multi-center/multi-moment description based on the distributed multipole analysis. For a broader ligand-binding study to test the multi-center/multi-moment electrostatics, HIV-I protease is a suitable system because a variety of experimentally determined binding constants for chemically different ligands are available. Reactive MD 6.EU FP Rahmenprogramm Research Project | 1 Project MembersDescribing chemical reactions with force fields is of funamental importance. Here we develop a Force-field based method that is able to describe the energetics and reactions involving transition metals relevant to hydrogenation reactions. 1 1 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 8 foundShow per page10 10 20 50 Intermolecular Interactions and the Role of Dynamics for Chemical Reactions in Complex Systems Research Project | 1 Project MembersThe goal of this project is to develop, implement and applycomputational strategies to characterize, understand and predictproperties of complex systems at a molecular level. To this end,computational techniques including multipolar (MTP) force fields,adiabatic reactive molecular dynamics (ARMD) simulations, andmolecular mechanics with proton transfer (MMPT) are used and furtherdeveloped. Multipolar force fields will be extended to routinespectroscopic applications such as 1- and 2-dimensional infraredspectroscopies. This will be applied to spectroscopic probes,primarily nitriles (-CN), which are sensitive environmental probes forprotein interiors. Fluctuating MTPs will be used to study the 1d- and2d-IR spectroscopy of-CN-containing inhibitors in human aldosereductase (hALR2) and benzonitrile in Lysozyme. Multiplesurface-ARMD will be combined with the fewest switching surfacehopping (FSSH) methodology for investigating nonadiabatic effects inchemical dynamics. This will considerably extend the range ofapplicability for MS-ARMD. Initial applications concernphotodissociation and recombination of ICN in solution and O2formation in amorphous ice at low temperatures. In a next step, thestructural and solvent dynamics upon oxidation from Cu(I) to Cu(II) incopper-phenanthroline complexes will be investigated. Also, standardARMD simulations will be used to study multiple-ligand dynamics in theactive site of truncated Hemoglobin N which is responsible fordenitrification. Molecular mechanics with proton transfer will becombined with multi state-ARMD to investigate proton transfer in thecondensed phase on extended time scales. Computationally efficientevaluation of accurate energy functions is particularly important whenusing it for multidimensional spectroscopy which typically requiresextensive conformational sampling to converge the frequency frequencycorrelation function. The developments will allow atomisticallyrefined simulations of the recently recorded 2d-IR spectrum of theexcess proton in liquid water. The present proposal involves tworesearch themes: reactive simulations in the condensed phase andcomputational vibrational spectroscopy which both require accuraterepresentations of the intermolecular interactions. International Research Training Group IRTG 1038 "Catalysts and Catylytic Reactions for Organic Synthesis. Research Project | 5 Project MembersUnder the roof of the International Research Training Group "Catalysts and Catalytic Reactions for Organic Synthesis" (IRTG 1038) six research groups from the Faculty of Chemistry, Pharmacy and Earth Sciences of the University of Freiburg i. Br. and five research groups from the Department of Chemistry of the University of Basel will combine their research and teaching activities in the field of catalysts and catalytic reactions for organic synthesis. Intensive bilateral collaboration will be ensured by the formation of joint research projects. The scientific research program encompasses all important areas of catalytic organic synthesis, such as catalyst development including combinatorial methods employing self-assembly catalysts, peptide-based organocatalysts and mass spectrometric catalyst screening, enzyme catalysis, catalytic reaction cascade development, asymmetric catalysts based on DNA templates, position-selective cross-coupling of multifunctional building blocks, and application to total synthesis of biologically relevant target molecules. Furthermore, theoretical and experimental methods will be implemented in order to get a deeper understanding of new catalyst systems and the mechanism of catalytic reactions. The International Research Training Group will provide the students with a vibrant research atmosphere and with a qualification program to develop a thorough knowledge of catalysts and catalytic reactions and their application to organic synthesis. The incorporation of industrial experts in the qualification program will ensure practical relevance and will demonstrate the importance of catalysts and catalytic reactions in the chemical and pharmaceutical industry. Optimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology:Theoretical and Practical Aspects Research Project | 3 Project MembersOptimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology: Theoretical and Practical Aspects In the past three decades, homogeneous and enzymatic catalysis have evolved independently to provide the necessary tools for the synthesis of high value added products. These two approaches are complementary in many respects. With the aim of exploiting the advantages of both fields, artificial metalloenzymes have recently attracted increasing attention. Such hybrid catalysts result from combining an organometallic moiety, typical of homogeneous catalysts, with a protein, reminiscent of an enzyme. Following this approach, several artificial metalloenzymes have been designed, optimized and structurally characterized. Within this project, it is proposed to combining both in-silico (computer-based) and in-vitro (experiment) screening of artificial metalloenzymes. For this purpose, mixed quantum mechanical/classical mechanics (QM/MM) calculations of artificial ketoreductases based on the biotin-avidin technology will be carried out. Because QM/MM is computationally a very demanding technique, also force field-based approaches will be further developed. One of them - VALBOND-TRANS - is specifically designed for treating metal centers in particular bonding topologies. Until now, VT has only been parametrized for octahedral complexes and we seek to extend this to square planar compounds. Finally, the insight obtained from the computational studies will be applied towards the chemogenetic optimization of artificial keto-reductases This project aims at providing alternative catalytic solutions with potentially broad (industrial) applications. Artifical enzymes have the potential to combine some of the attractive features of both homogeneous and enzymatic catalysis. Here we try to pursue a targeted approach that is inspired by how nature addresses such problems and that is guided by reliable computations. Weakly Coordinatting Anions and Bidentate Lewis Acids - New Possibilities in Catalysis. Research Project | 3 Project MembersToday's world is unthinkable without catalysis and efficient catalysts. Although the focus of Organic Chemistry is truly on carbon, catalysis involves in nearly all cases other elements, especially transition metals. In this research project, which is part of the International Research Training Group IRTG 1038 "Catalysis and Catalytic Reactions for Organic Synthesis", we want to investigate two kinds of catalytic processes. The first one deals with the influence of weakly coordinating anions (WCAs) on transition metal, especially gold catalyzed reactions, and the second one is the use of bidentate Lewis acids as catalysts in organic synthesis. Due to constrains in resources only the second part can be realized. The multidisciplinary nature of the problems, ranging from organic synthesis and inorganic chemistry to molecular interactions between complex solvent, catalyst and substrate is re-flected in a joint effort by two groups from the University of Basel, Dr. Hermann Wegner (or-ganic synthesis and catalysis) and Prof. Markus Meuwly (computational and theoretical chem-istry), and one group from the University of Freiburg, Prof. Ingo Krossing (inorganic chemistry). Bidentate Lewis acids have hardly applied as catalysts in organic synthesis up to now. Here, a first proof of principle has been shown in the Wegner group for an Inverse Electron Demanding Diels-Alder (IEDDA) reaction of 1,2-diazene to 1,2-substituted aryl compounds. Using spectroscopic as well as computational tools should clarify the exact mechanism, influences and other parameter on the reaction. By this approach we will shine light on this interesting class of unexplored catalysts and open up the way for optimizing the IEDDA to a general applicable method for the preparation of 1,2-substituted arenes. With a detailed picture of the transformation the knowledge will be used to find other application for bidentate Lewis acids in catalysis, e.g. other challenging cycloaddition reactions or aldol type chemistry. Insights into bidentate Lewis acids as catalysts in organic synthesis will be a benefit for the whole community and stimulate the development greatly in this area. The multidisciplinary approach offers the enormous advantage to tackle the problem from various dimensions. As this research project is part of a ProDoc program it has the great advantage to give the par-ticipating students a deep insight into various disciplines and how to combine them to address questions in catalysis. Computational Analytical Chemistry: Research Project | 1 Project MembersThe goal of the project is to develop quantitative numerical methods and computational strategies to understand the physico-chemical properties of reversed phase liquid chromatography that lead to selectivity and retention. Based on our initial investigation and characterization of a realistic chromatographic system the influence of different functionalizations of the stationary phase will be investigated to provide further information about the selectivity of alkyl columns. In a next step, based on the detailed atomistic simulations which have already been carried out in our group and which have been validated in view of experimental results, more efficient representations of the intermolecular interactions are developed and used in coarse grained molecular dynamics simulations. Describing electrostatic interactions with distributed multipoles of higher order (up to hexadecapole) has been shown in our group to lead to a quantitative understanding of the energetics and dynamics in condensed-phase simulations. Such extensions and generalizations will also be pursued for the coarse grained simulations. Reversed Phase Liquid Chromatography (RPLC) is a widely used analytical technique in pharmaceutical separations, the food industry, in life-science applications (peptide and protein separation), and in the analysis of industrial polymers. Despite this importance (up to 90 % of all analytical separations on low molecular weight samples use RPLC) the molecular mechanisms for retention and selectivity are still unclear. Important questions concern, for example, the understanding of solute-solvent interactions, the influence of varying acidities of the solvent and the role of the stationary phase in creating a microheterogeneous environment and ultimately to unravel the origin of selectivity of columns with different functionalizations and solvent compositions. Such questions are ideally suited to be pursued with computer simulations which are also validated in view of experimental data. Atomistic Modelling and Experimental Validation of Enzyme-Inhibitor Interactions of Dengue Fever Virus Methyltransferase: Towards new approaches to target neglected tropical diseases. Research Project | 4 Project MembersDengue fever is a viral infectious disease that is prevalent in tropical regions. It is transmitted by mosquitoes and annually affects 50 to 100 million people worldwide. No vaccinations or specific drug treatments are available. Several of the virus' proteins are essential for its pathogenicity and are required by the virus to reproduce in host cells. In cases where three-dimensional structural models of the binding site of the proteins are known, computer simulations (i.e. virtual screening or molecular docking) can be used to simulate possible interaction between these proteins and small inhibitor molecules with the potential to become drug candidates. However, current algorithms used in virtual screening must make a number of approximations in order to be able to screen a large number of compounds within reasonable time. In contrast, atomistic simulations based on the physicochemical properties of molecules using Newton's laws of motion to determine the strength of binding between ligand and receptor molecules can provide more accurate, but computationally more demanding, predictions of the affinity with which a molecule binds to specific site in a protein. In this study, we focus our computational work on simulating the binding of small-molecule inhibitors to the viral enzyme NS5 methyltransferase. In a first step, a library of commercially available chemical compounds is searched by virtual screening for molecules likely to bind to the viral enzyme. Chemical compounds emerging from this study as possible inhibitors of dengue methyltransferase will be tested in biochemical and biological assays for their ability to inhibit viral replication in cultured cells. For this point, we are closely collaborating with the Novartis Institute for Tropical Diseases in Singapore. The results of the experimental measurements will in return increase our understanding of the physicochemical interactions governing methyltransferase inhibitor interactions and allow us to improve the accuracy of our molecular modeling simulations by calibrating interaction parameters with experimental binding affinities. Despite the clinical interest in MTase as drug target, little is known about the enzymatic mechanism of the methyl transfer reaction of this class of methyl transferases. In the second phase of the project, we have therefore focused on detailed molecular dynamics simulations of the transfer reaction. We moreover hope that this research will contribute to the discovery of new lead compounds against neglected tropical diseases, leading to the development of drugs that are offered at cost in the affected countries. Intermolecular Interactions and the Role Research Project | 1 Project MembersThe goal of the project is to develop numerical methods and computational strategies to understand the energetics and dynamics of chemical reactions in complex environments and to apply them to chemically and biologically interesting systems. Using a combination of reactive molecular dynamics (RMD), improved force fields, potential energy surface ``morphing'' procedures, and electronic structure calculations, reactions including hydrogen/proton-transfer, ligand-binding and electron-coupled proton transfer are investigated at a quantitative level. The reactive molecular dynamics method, which was developed for rebinding reactions of diatomic ligands to myoglobin, I) will be generalized to treat enzymatic and rebinding reactions between arbitrary ligands and substrates and II) will be extended to electron-transfer reactions. Specific applications of reactive molecular dynamics include ligand binding in myoglobin, Cytochrome P450, and Azotobacter Vinelandii Ferredoxin I (FdI). These are systems for which detailed experimental data and information from previous simulations is available. More reliable intermolecular interaction potentials will be derived by ``morphing'' suitable zeroth-order potential energy surfaces. This strategy will be applied to problems from molecular spectroscopy to proton transfer in proteins (e.g. FdI). To improve the description of the electrostatic interaction between ligands and the surrounding protein in ligand-binding studies we currently develop and implement a multi-center/multi-moment description based on the distributed multipole analysis. For a broader ligand-binding study to test the multi-center/multi-moment electrostatics, HIV-I protease is a suitable system because a variety of experimentally determined binding constants for chemically different ligands are available. Reactive MD 6.EU FP Rahmenprogramm Research Project | 1 Project MembersDescribing chemical reactions with force fields is of funamental importance. Here we develop a Force-field based method that is able to describe the energetics and reactions involving transition metals relevant to hydrogenation reactions. 1 1
Intermolecular Interactions and the Role of Dynamics for Chemical Reactions in Complex Systems Research Project | 1 Project MembersThe goal of this project is to develop, implement and applycomputational strategies to characterize, understand and predictproperties of complex systems at a molecular level. To this end,computational techniques including multipolar (MTP) force fields,adiabatic reactive molecular dynamics (ARMD) simulations, andmolecular mechanics with proton transfer (MMPT) are used and furtherdeveloped. Multipolar force fields will be extended to routinespectroscopic applications such as 1- and 2-dimensional infraredspectroscopies. This will be applied to spectroscopic probes,primarily nitriles (-CN), which are sensitive environmental probes forprotein interiors. Fluctuating MTPs will be used to study the 1d- and2d-IR spectroscopy of-CN-containing inhibitors in human aldosereductase (hALR2) and benzonitrile in Lysozyme. Multiplesurface-ARMD will be combined with the fewest switching surfacehopping (FSSH) methodology for investigating nonadiabatic effects inchemical dynamics. This will considerably extend the range ofapplicability for MS-ARMD. Initial applications concernphotodissociation and recombination of ICN in solution and O2formation in amorphous ice at low temperatures. In a next step, thestructural and solvent dynamics upon oxidation from Cu(I) to Cu(II) incopper-phenanthroline complexes will be investigated. Also, standardARMD simulations will be used to study multiple-ligand dynamics in theactive site of truncated Hemoglobin N which is responsible fordenitrification. Molecular mechanics with proton transfer will becombined with multi state-ARMD to investigate proton transfer in thecondensed phase on extended time scales. Computationally efficientevaluation of accurate energy functions is particularly important whenusing it for multidimensional spectroscopy which typically requiresextensive conformational sampling to converge the frequency frequencycorrelation function. The developments will allow atomisticallyrefined simulations of the recently recorded 2d-IR spectrum of theexcess proton in liquid water. The present proposal involves tworesearch themes: reactive simulations in the condensed phase andcomputational vibrational spectroscopy which both require accuraterepresentations of the intermolecular interactions.
International Research Training Group IRTG 1038 "Catalysts and Catylytic Reactions for Organic Synthesis. Research Project | 5 Project MembersUnder the roof of the International Research Training Group "Catalysts and Catalytic Reactions for Organic Synthesis" (IRTG 1038) six research groups from the Faculty of Chemistry, Pharmacy and Earth Sciences of the University of Freiburg i. Br. and five research groups from the Department of Chemistry of the University of Basel will combine their research and teaching activities in the field of catalysts and catalytic reactions for organic synthesis. Intensive bilateral collaboration will be ensured by the formation of joint research projects. The scientific research program encompasses all important areas of catalytic organic synthesis, such as catalyst development including combinatorial methods employing self-assembly catalysts, peptide-based organocatalysts and mass spectrometric catalyst screening, enzyme catalysis, catalytic reaction cascade development, asymmetric catalysts based on DNA templates, position-selective cross-coupling of multifunctional building blocks, and application to total synthesis of biologically relevant target molecules. Furthermore, theoretical and experimental methods will be implemented in order to get a deeper understanding of new catalyst systems and the mechanism of catalytic reactions. The International Research Training Group will provide the students with a vibrant research atmosphere and with a qualification program to develop a thorough knowledge of catalysts and catalytic reactions and their application to organic synthesis. The incorporation of industrial experts in the qualification program will ensure practical relevance and will demonstrate the importance of catalysts and catalytic reactions in the chemical and pharmaceutical industry.
Optimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology:Theoretical and Practical Aspects Research Project | 3 Project MembersOptimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology: Theoretical and Practical Aspects In the past three decades, homogeneous and enzymatic catalysis have evolved independently to provide the necessary tools for the synthesis of high value added products. These two approaches are complementary in many respects. With the aim of exploiting the advantages of both fields, artificial metalloenzymes have recently attracted increasing attention. Such hybrid catalysts result from combining an organometallic moiety, typical of homogeneous catalysts, with a protein, reminiscent of an enzyme. Following this approach, several artificial metalloenzymes have been designed, optimized and structurally characterized. Within this project, it is proposed to combining both in-silico (computer-based) and in-vitro (experiment) screening of artificial metalloenzymes. For this purpose, mixed quantum mechanical/classical mechanics (QM/MM) calculations of artificial ketoreductases based on the biotin-avidin technology will be carried out. Because QM/MM is computationally a very demanding technique, also force field-based approaches will be further developed. One of them - VALBOND-TRANS - is specifically designed for treating metal centers in particular bonding topologies. Until now, VT has only been parametrized for octahedral complexes and we seek to extend this to square planar compounds. Finally, the insight obtained from the computational studies will be applied towards the chemogenetic optimization of artificial keto-reductases This project aims at providing alternative catalytic solutions with potentially broad (industrial) applications. Artifical enzymes have the potential to combine some of the attractive features of both homogeneous and enzymatic catalysis. Here we try to pursue a targeted approach that is inspired by how nature addresses such problems and that is guided by reliable computations.
Weakly Coordinatting Anions and Bidentate Lewis Acids - New Possibilities in Catalysis. Research Project | 3 Project MembersToday's world is unthinkable without catalysis and efficient catalysts. Although the focus of Organic Chemistry is truly on carbon, catalysis involves in nearly all cases other elements, especially transition metals. In this research project, which is part of the International Research Training Group IRTG 1038 "Catalysis and Catalytic Reactions for Organic Synthesis", we want to investigate two kinds of catalytic processes. The first one deals with the influence of weakly coordinating anions (WCAs) on transition metal, especially gold catalyzed reactions, and the second one is the use of bidentate Lewis acids as catalysts in organic synthesis. Due to constrains in resources only the second part can be realized. The multidisciplinary nature of the problems, ranging from organic synthesis and inorganic chemistry to molecular interactions between complex solvent, catalyst and substrate is re-flected in a joint effort by two groups from the University of Basel, Dr. Hermann Wegner (or-ganic synthesis and catalysis) and Prof. Markus Meuwly (computational and theoretical chem-istry), and one group from the University of Freiburg, Prof. Ingo Krossing (inorganic chemistry). Bidentate Lewis acids have hardly applied as catalysts in organic synthesis up to now. Here, a first proof of principle has been shown in the Wegner group for an Inverse Electron Demanding Diels-Alder (IEDDA) reaction of 1,2-diazene to 1,2-substituted aryl compounds. Using spectroscopic as well as computational tools should clarify the exact mechanism, influences and other parameter on the reaction. By this approach we will shine light on this interesting class of unexplored catalysts and open up the way for optimizing the IEDDA to a general applicable method for the preparation of 1,2-substituted arenes. With a detailed picture of the transformation the knowledge will be used to find other application for bidentate Lewis acids in catalysis, e.g. other challenging cycloaddition reactions or aldol type chemistry. Insights into bidentate Lewis acids as catalysts in organic synthesis will be a benefit for the whole community and stimulate the development greatly in this area. The multidisciplinary approach offers the enormous advantage to tackle the problem from various dimensions. As this research project is part of a ProDoc program it has the great advantage to give the par-ticipating students a deep insight into various disciplines and how to combine them to address questions in catalysis.
Computational Analytical Chemistry: Research Project | 1 Project MembersThe goal of the project is to develop quantitative numerical methods and computational strategies to understand the physico-chemical properties of reversed phase liquid chromatography that lead to selectivity and retention. Based on our initial investigation and characterization of a realistic chromatographic system the influence of different functionalizations of the stationary phase will be investigated to provide further information about the selectivity of alkyl columns. In a next step, based on the detailed atomistic simulations which have already been carried out in our group and which have been validated in view of experimental results, more efficient representations of the intermolecular interactions are developed and used in coarse grained molecular dynamics simulations. Describing electrostatic interactions with distributed multipoles of higher order (up to hexadecapole) has been shown in our group to lead to a quantitative understanding of the energetics and dynamics in condensed-phase simulations. Such extensions and generalizations will also be pursued for the coarse grained simulations. Reversed Phase Liquid Chromatography (RPLC) is a widely used analytical technique in pharmaceutical separations, the food industry, in life-science applications (peptide and protein separation), and in the analysis of industrial polymers. Despite this importance (up to 90 % of all analytical separations on low molecular weight samples use RPLC) the molecular mechanisms for retention and selectivity are still unclear. Important questions concern, for example, the understanding of solute-solvent interactions, the influence of varying acidities of the solvent and the role of the stationary phase in creating a microheterogeneous environment and ultimately to unravel the origin of selectivity of columns with different functionalizations and solvent compositions. Such questions are ideally suited to be pursued with computer simulations which are also validated in view of experimental data.
Atomistic Modelling and Experimental Validation of Enzyme-Inhibitor Interactions of Dengue Fever Virus Methyltransferase: Towards new approaches to target neglected tropical diseases. Research Project | 4 Project MembersDengue fever is a viral infectious disease that is prevalent in tropical regions. It is transmitted by mosquitoes and annually affects 50 to 100 million people worldwide. No vaccinations or specific drug treatments are available. Several of the virus' proteins are essential for its pathogenicity and are required by the virus to reproduce in host cells. In cases where three-dimensional structural models of the binding site of the proteins are known, computer simulations (i.e. virtual screening or molecular docking) can be used to simulate possible interaction between these proteins and small inhibitor molecules with the potential to become drug candidates. However, current algorithms used in virtual screening must make a number of approximations in order to be able to screen a large number of compounds within reasonable time. In contrast, atomistic simulations based on the physicochemical properties of molecules using Newton's laws of motion to determine the strength of binding between ligand and receptor molecules can provide more accurate, but computationally more demanding, predictions of the affinity with which a molecule binds to specific site in a protein. In this study, we focus our computational work on simulating the binding of small-molecule inhibitors to the viral enzyme NS5 methyltransferase. In a first step, a library of commercially available chemical compounds is searched by virtual screening for molecules likely to bind to the viral enzyme. Chemical compounds emerging from this study as possible inhibitors of dengue methyltransferase will be tested in biochemical and biological assays for their ability to inhibit viral replication in cultured cells. For this point, we are closely collaborating with the Novartis Institute for Tropical Diseases in Singapore. The results of the experimental measurements will in return increase our understanding of the physicochemical interactions governing methyltransferase inhibitor interactions and allow us to improve the accuracy of our molecular modeling simulations by calibrating interaction parameters with experimental binding affinities. Despite the clinical interest in MTase as drug target, little is known about the enzymatic mechanism of the methyl transfer reaction of this class of methyl transferases. In the second phase of the project, we have therefore focused on detailed molecular dynamics simulations of the transfer reaction. We moreover hope that this research will contribute to the discovery of new lead compounds against neglected tropical diseases, leading to the development of drugs that are offered at cost in the affected countries.
Intermolecular Interactions and the Role Research Project | 1 Project MembersThe goal of the project is to develop numerical methods and computational strategies to understand the energetics and dynamics of chemical reactions in complex environments and to apply them to chemically and biologically interesting systems. Using a combination of reactive molecular dynamics (RMD), improved force fields, potential energy surface ``morphing'' procedures, and electronic structure calculations, reactions including hydrogen/proton-transfer, ligand-binding and electron-coupled proton transfer are investigated at a quantitative level. The reactive molecular dynamics method, which was developed for rebinding reactions of diatomic ligands to myoglobin, I) will be generalized to treat enzymatic and rebinding reactions between arbitrary ligands and substrates and II) will be extended to electron-transfer reactions. Specific applications of reactive molecular dynamics include ligand binding in myoglobin, Cytochrome P450, and Azotobacter Vinelandii Ferredoxin I (FdI). These are systems for which detailed experimental data and information from previous simulations is available. More reliable intermolecular interaction potentials will be derived by ``morphing'' suitable zeroth-order potential energy surfaces. This strategy will be applied to problems from molecular spectroscopy to proton transfer in proteins (e.g. FdI). To improve the description of the electrostatic interaction between ligands and the surrounding protein in ligand-binding studies we currently develop and implement a multi-center/multi-moment description based on the distributed multipole analysis. For a broader ligand-binding study to test the multi-center/multi-moment electrostatics, HIV-I protease is a suitable system because a variety of experimentally determined binding constants for chemically different ligands are available.
Reactive MD 6.EU FP Rahmenprogramm Research Project | 1 Project MembersDescribing chemical reactions with force fields is of funamental importance. Here we develop a Force-field based method that is able to describe the energetics and reactions involving transition metals relevant to hydrogenation reactions.
