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| Warshel has made major contributions in introducing computational methods for studying structure-function correlation in biological molecules. He pioneered (and co-pioneered) simulation software, as well as key methods and concepts for microscopic studies of the functional properties of biological molecules, including the Cartesian-based force field program CFF <ref name=cons1>{{cite journal |author=Lifson S, Warshel A.|year= 1968| title=A Consistent Force Field for Calculation on Conformations, Vibrational Spectra and Enthalpies of Cycloalkanes and n-Alkane Molecules| journal = J. Phys. Chem.| volume=49| pages=5116| doi=10.1063/1.1670007 |issue=11}}</ref><ref name=cons2>{{cite journal |author=Warshel A, Lifson S.|year=1970| title=Consistent Force Field Calculations. II. Crystal Structure, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations and Enthalpies of Alkanes| journal= J. Chem. Phys.| volume=53| pages=582| doi=10.1063/1.1674031 |issue=2}}</ref><ref name=lev01> {{cite journal|author=Levitt, M|year=2001|title=The birth of computational structural biology|journal=Nat. Struct. Biol.|volume=8|pages=392–393|doi=10.1038/87545|pmid=11323711}}</ref>, the QM/MM method for simulating enzymatic reactions, <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>, molecular dynamics simulations of biological molecules <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref><ref name=moldyn>{{cite journal |author=Warshel A.| year=2002|title=Molecular Dynamics Simulations of Biological Reactions| journal=Acc. Chem. Res.| volume=35|pages=385–395|doi=10.1021/ar010033z |pmid=12069623 |issue=6}}</ref>, microscopic electrostatic models for proteins <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref><ref name=russ>{{cite journal| author=Warshel A, Russell S T.| year=1984|title=Calculations of Electrostatic Interactions in Biological Systems and in Solutions| journal=Quart. Rev. Biophys.| volume=17|pages=283| doi=10.1017/S0033583500005333| issue=3}}</ref>, free energy perturbations in proteins <ref name=simul>{{cite journal|author=Warshel A|year=1984|title=Simulating the Energetics and Dynamics of Enzymatic Reactions|journal=Pontificiae Academiae Scientiarum Scripta Varia| volume=55|pages=60}}</ref>, and other key advances. |
Warshel has made major contributions in introducing computational methods for studying structure-function correlation in biological molecules. He pioneered (and co-pioneered) simulation software, as well as key methods and concepts for microscopic studies of the functional properties of biological molecules, including the Cartesian-based force field program CFF <ref name=cons1>{{cite journal |author=Lifson S, Warshel A.|year= 1968| title=A Consistent Force Field for Calculation on Conformations, Vibrational Spectra and Enthalpies of Cycloalkanes and n-Alkane Molecules| journal = J. Phys. Chem.| volume=49| pages=5116| doi=10.1063/1.1670007 |issue=11}}</ref><ref name=cons2>{{cite journal |author=Warshel A, Lifson S.|year=1970| title=Consistent Force Field Calculations. II. Crystal Structure, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations and Enthalpies of Alkanes| journal= J. Chem. Phys.| volume=53| pages=582| doi=10.1063/1.1674031 |issue=2}}</ref><ref name=lev01> {{cite journal|author=Levitt, M|year=2001|title=The birth of computational structural biology|journal=Nat. Struct. Biol.|volume=8|pages=392–393|doi=10.1038/87545|pmid=11323711}}</ref>, the QM/MM method for simulating enzymatic reactions, <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>, molecular dynamics simulations of biological molecules <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref><ref name=moldyn>{{cite journal |author=Warshel A.| year=2002|title=Molecular Dynamics Simulations of Biological Reactions| journal=Acc. Chem. Res.| volume=35|pages=385–395|doi=10.1021/ar010033z |pmid=12069623 |issue=6}}</ref>, microscopic electrostatic models for proteins <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref><ref name=russ>{{cite journal| author=Warshel A, Russell S T.| year=1984|title=Calculations of Electrostatic Interactions in Biological Systems and in Solutions| journal=Quart. Rev. Biophys.| volume=17|pages=283| doi=10.1017/S0033583500005333| issue=3}}</ref>, free energy perturbations in proteins <ref name=simul>{{cite journal|author=Warshel A|year=1984|title=Simulating the Energetics and Dynamics of Enzymatic Reactions|journal=Pontificiae Academiae Scientiarum Scripta Varia| volume=55|pages=60}}</ref>, and other key advances. Further information can be found at . | ||
| === Laying the Foundation for Many Modern Computer Simulations of Protein Function === | |||
| Warshel introduced some of the most crucial approaches in modeling protein function. He also pioneered (and co-pioneered) key studies and directions that turned out eventually to be essential for quantifying protein function. These include: | |||
| *Co-introducing (1976) the combined quantum mechanical / molecular mechanical (QM/MM) approach, which has become the basis of the field of computational enzymology <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>. | |||
| *Performing (1976) the first molecular dynamics (MD) simulation of a biological process <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref><ref name=moldyn>{{cite journal |author=Warshel A.| year=2002|title=Molecular Dynamics Simulations of Biological Reactions| journal=Acc. Chem. Res.| volume=35|pages=385–395|doi=10.1021/ar010033z |pmid=12069623 |issue=6}}</ref>. | |||
| *Co-introducing the simplified protein-folding model (1975) <ref>{{cite journal |author=Levitt M, Warshel A.| year=1975| title=Computer Simulations of Protein Folding| journal=Nature| volume=253|pages=694–8| doi=10.1038/253694a0 |pmid=1167625 |issue=5494}}</ref>. | |||
| *Introducing (1981) computer-based microscopic thermodynamic cycles in biology (11). | |||
| *Introducing (1981) consistent calculations of spectral shifts, as well as consistent microscopic calculations of pKas in proteins <ref>{{cite journal| author=Warshel A| title=Calculations of Enzymic Reactions: Calculations of pKa, Proton Transfer Reactions, and General Acid Catalysis Reactions in Enzymes| journal=Biochemistry| volume=20|pages=3167–77| doi=10.1021/bi00514a028| year=1981| pmid=7248277| issue=11}}</ref>. | |||
| *Performing (1984) the first free-energy perturbation calculations in proteins <ref name=simul>{{cite journal|author=Warshel A|year=1984|title=Simulating the Energetics and Dynamics of Enzymatic Reactions|journal=Pontificiae Academiae Scientiarum Scripta Varia| volume=55|pages=60}}</ref>. | |||
| *Introducing (1986) consistent structure-based calculations of the redox potentials of proteins <ref>{{cite journal| author=Churg, A K, Warshel A| title=Control of the redox potential of cytochrome and microscopic dielectric effects in proteins| journal=Biochemistry| volume=25|pages=1675–1681| doi=10.1021/bi00355a035| year=1986| issue=7}}</ref>. | |||
| *Introducing (1991) simulations of quantum-mechanical tunneling in enzymatic reactions and in solution <ref name=yadjpc>{{cite journal| author=Hwang J K, Chu Z T, Yadav A, Warshel A| title=Simulations of quantum mechanical corrections for rate constants of hydride-transfer reactions in enzymes and solutions| journal=J Phys Chem| volume=95|pages=8445–8448| doi=10.1021/j100175a009| year=1991| issue=22}}</ref>. | |||
| *Introducing (1992) microscopic linear response approximation (LRA) calculations of absolute binding free energies <ref name=engg>{{cite journal|author=Lee F S, Chu Z T, Bolger M B, Warshel A|title=Calculations of antibody-antigen interactions: microscopic and semi-microscopic evaluation of the free energies of binding of phosphorylcholine analogs to McPC603|journal=Protein Engg|year=1992|volume=5|issue=3|pages=215–228|doi=10.1093/protein/5.3.215}}</ref>. | |||
| *Introducing (1999) simulations of time-dependent proton transport in proteins <ref> {{cite journal|title=Simulating proton translocations in proteins: Probing proton transfer pathways in the Rhodobacter sphaeroides reaction center|author=Sham Y Y, Muegge I, Warshel A|year=1999|doi=10.1002/(SICI)1097-0134(19990901)36:4<484::AID-PROT13>3.0.CO;2-R|journal=Proteins: Structure, Function, and Bioinformatics|volume=36|issue=4|pages=484–500}}</ref> <ref>{{cite journal|title=Monte Carlo simulations of proton pumps: On the working principles of the biological valve that controls proton pumping in cytochrome c oxidase|author=Olsson M H M, Warshel A|year=2006|journal=Proc Natl Acad Sci USA|doi=10.1073/pnas.0510860103|volume=103|issue=17|pages=6500–6505}}</ref> | |||
| === Quantifying the Molecular Basis for Enzyme Catalysis === | |||
| In 1976, Warshel and Levitt pioneered calculations that considered an entire enzyme-substrate complex in solution, and evaluated the catalytic effect of this system <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>. This work introduced the hybrid quantum mechanical / molecular mechanical (QM/MM) approach, which has since become a major scientific discipline. Warshel’s subsequent studies paved the way for the quantitative modeling of enzyme reactions. He has pioneered simulations of the dynamics of enzymatic reactions, and introduced the powerful free energy perturbation method for the modeling of enzymatic reactions. Warshel proposed and quantitatively established that enzyme catalysis is due to the fact that the active site dipoles are already preoriented towards the charge distribution of the transition state <ref name=getics>{{cite journal| author=Warshel A| year=1978| title=Energetics of enzyme catalysis| journal=Proc. Natl. Acad. Sci. USA| volume=75| pages=5250–4| doi=10.1073/pnas.75.11.5250| pmid=281676| issue=11| pmc=392938}}</ref>. His key advances in this direction include: | |||
| *Introducing (1976) the combined quantum mechanical / molecular mechanical (QM/MM) approach, which has since become the basis of the field of Computational Enzymology <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>. | |||
| *Proposing (1978) and demonstrating that polar preorganization is the key factor in enzyme catalysis, and rationalizing the inverted catalysis/stability relationship <ref name=getics>{{cite journal| author=Warshel A| year=1978| title=Energetics of enzyme catalysis| journal=Proc. Natl. Acad. Sci. USA| volume=75| pages=5250–4| doi=10.1073/pnas.75.11.5250| pmid=281676| issue=11| pmc=392938}}</ref>. | |||
| *Pioneering free energy perturbation (1984) calculations of enzymatic reactions, which were subsequently extended to the reactivity of many key enzyme families <ref name=simul>{{cite journal|author=Warshel A|year=1984|title=Simulating the Energetics and Dynamics of Enzymatic Reactions|journal=Pontificiae Academiae Scientiarum Scripta Varia| volume=55|pages=60}}</ref> <ref name=chemrev> {{cite journal|title=Electrostatic Basis for Enzyme Catalysis|author=Warshel A, Sharma P K, Kato M, Xiang Y, Liu H, Olsson M H M|journal=Chemical Reviews| year=2006|volume=106|issue=8| pages=3210–3235|doi=10.1021/cr0503106|pmid=16895325}}</ref>. | |||
| *Performing (1984) the first simulation of dynamical contributions to enzyme catalysis. | |||
| *Quantifying (2000) entropic contributions to enzyme catalysis <ref>{{cite journal|doi=10.1073/pnas.97.22.11899|year=2000|volume =97|issue=22|pages= 11899–11904|title=How important are entropic contributions to enzyme catalysis?|author=Villà J, Štrajbl M,Glennon T M,Sham Y Y,Chu Z T, Warshel A|pmid=11050223|pmc=17266}} </ref>. | |||
| *Systematically simulating (1980-2011 ) almost all of the available catalytic proposals, and demonstrating that most enzymes catalyze their reactions by electrostatic effects <ref name=chemrev> {{cite journal|title=Electrostatic Basis for Enzyme Catalysis|author=Warshel A, Sharma P K, Kato M, Xiang Y, Liu H, Olsson M H M|journal=Chemical Reviews|year=2006|volume=106|issue=8| pages=3210–3235|doi=10.1021/cr0503106|pmid=16895325}}</ref> <ref> {{cite book|title= Computer Simulation of Chemical Reactions in Enzymes and Solutions|author= Warshel A|publisher=John Wiley & Sons|year=1991|place=New York}} </ref> | |||
| === Pioneering MD Simulations of Biological Functions === | |||
| The first use of MD in studying a biological process was presented by Warshel in 1976 <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref>. His simulations of the primary event in the vision process correctly predicted the photoisomerization time of rhodopsin. This prediction has been subsequently experimentally confirmed <ref name=mathis>{{cite journal|journal=Science|year=1994| | |||
| volume=266|issue=5184|pages=422–424|doi=10.1126/science.7939680|title=Vibrationally coherent photochemistry in the femtosecond primary event of vision|author=Wang Q, Schoenlein R W, Peteanu L A, Mathies R A, Shank C V}}</ref> <ref name=cn10> {{cite journal|Volume=88|Issue=39|pages=11| year=2010|title= Probing Key Vision Event|author=Arnaud C|journal = Chemical and Engineering News}}</ref>. Warshel also used the same semiclassical approach in pioneering simulations of the primary electron transfer in photosynthesis <ref name=crei> {{cite journal| title=Simulating the dynamics of the primary charge separation process in bacterial photosynthesis|author=Creighton S, Hwang J K, Warshel A, Parson W W ,Norris J|journal=Biochemistry|year=1988|volume=27|issue=2|pages=774–781|doi= 10.1021/bi00402a043}}</ref>. Warshel’s 1976 <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref> <ref> {{cite journal|journal= J Phys Chem B|authors= Warshel A, Chu Z T|year=2001|volume=105|issue=40|pages=9857–9871|doi=10.1021/jp010704a|title=Nature of the Surface Crossing Process in Bacteriorhodopsin: Computer Simulations of the Quantum Dynamics of the Primary Photochemical Event}}</ref> simulations of photochemical processes also discovered a very large crossing probability, that reflected what is now known as the effect of conical intersections. This feature has been now confirmed in many photobiological reactions (e.g., <ref name = oliv>{{cite journal| doi=10.1073/pnas.0701732104|journal= Proc Natl Acad Sci USA|year=2007|volume=104|issue=19|pages=7764–7769|title=Tracking the excited-state time evolution of the visual pigment with multiconfigurational quantum chemistry|author= Frutos L M, Andruniów T, Santoro F,Ferré N, Olivucci M.}}</ref>. His key advances in this direction include: | |||
| *Simulating (1976) the first step in the vision process, and predicting that this step occurs in about 100fs, while finding that this step involves an enormous crossing probability <ref name="bicycle">{{cite journal |author=Warshel A.| year=1976| title=Bicycle-pedal Model for the First Step in the Vision Process| journal=Nature| volume=260|pages=679–83| doi=10.1038/260679a0 |pmid=1264239 |issue=5553}}</ref>. The predicted time has been since confirmed experimentally <ref name=mathis>{{cite journal| journal=Science| year=1994|volume=266| issue=5184|pages=422–424|doi=10.1126/science.7939680|title=Vibrationally coherent photochemistry in the femtosecond primary event of vision|author=Wang Q, Schoenlein R W, Peteanu L A, Mathies R A, Shank C V}}</ref> and other features of the calculations, like the large crossing probability (what is now known as a “conical intersection”) as well as the partially concerted isomerization path were eventually confirmed by ab initio QM/MM simulations <ref name = oliv>{{cite journal| doi=10.1073/pnas.0701732104|journal= Proc Natl Acad Sci USA|year=2007|volume=104|issue=19|pages=7764–7769|title=Tracking the excited-state time evolution of the visual pigment with multiconfigurational quantum chemistry|author= Frutos L M, Andruniów T, Santoro F,Ferré N, Olivucci M.}}</ref>. *Demonstrating (1984) that productive trajectories in enzymatic reactions take about 1ps <ref name=pnas84>{{cite journal|author=Warshel A|year=1984|title=Dynamics of Enzymatic Reactions|journal=Proc. Natl. Acad. Sci.USA|volume=81|issue=2|pages=444–448|doi=10.1073/pnas.81.2.444}}</ref>. | |||
| *Simulating (1985) the autocorrelation time that controls the protein response in charge transport processes . This prediction was eventually also experimentally confirmed (1988 (Find Experimnts) | |||
| === Laying the Basis for Microscopic Electrostatic Calculations of Proteins === | |||
| Warshel’s works paved the way for quantitative studies of electrostatic energies in proteins. He and his coworkers provided the first treatments that considered the entire contributions to the electrostatic free energies of proteins <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>. He also introduced the first simplified microscopic treatment of the energy of charges in solvated proteins <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref> and the first free energy perturbation study of a charge in a protein <ref name=suss>{{cite journal|author=Warshel A, Sussman F, King G.| year=1986|title=Free Energy of Charges in Solvated Proteins: Microscopic Calculations Using a Reversible Charging Process| journal=Biochemistry| volume=25|pages=8368–72|doi=10.1021/bi00374a006|pmid=2435316|issue=26}}</ref>. His models opened the way to realistic calculations of pKas, redox potentials and absolute binding free energies <ref name=bba>{{cite journal|author=Warshel A, Sharma P K, Kato M, Parson W W.| year=2006| title=Modeling Electrostatic Effects in Proteins| journal=Biochim. Biophys. Acta|volume=1764|pages=1647–1676|pmid=17049320|issue=11| doi=10.1016/j.bbapap.2006.08.007}}</ref> in proteins. His key advances in this direction include: | |||
| *Introducing (1976) consistent microscopic models of solvated proteins <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref>. | |||
| *Establishing (1978) the key role of the polarity of protein active sites <ref name=getics>{{cite journal| author=Warshel A| year=1978| title=Energetics of enzyme catalysis| journal=Proc. Natl. Acad. Sci. USA| volume=75| pages=5250–4| doi=10.1073/pnas.75.11.5250| pmid=281676| issue=11| pmc=392938}}</ref>. | |||
| *Establishing (1984) the desolvation penalty and the crucial compensation effects of the protein permanent dipoles, and quantifying the energetics of ion pairs in proteins <ref name=russ>{{cite journal| author=Warshel A, Russell S T.| year=1984|title=Calculations of Electrostatic Interactions in Biological Systems and in Solutions| journal=Quart. Rev. Biophys.| volume=17|pages=283| doi=10.1017/S0033583500005333| issue=3}}</ref> <ref name=bba>{{cite journal|author=Warshel A, Sharma P K, Kato M, Parson W W.| year=2006| title=Modeling Electrostatic Effects in Proteins| journal=Biochim. Biophys. Acta|volume=1764|pages=1647–1676|pmid=17049320|issue=11| doi=10.1016/j.bbapap.2006.08.007}}</ref>. | |||
| *Introducing (1986) free energy perturbation and LRA calculations (1992) of electrostatic energies in proteins <ref name=suss>{{cite journal|author=Warshel A, Sussman F, King G.| year=1986|title=Free Energy of Charges in Solvated Proteins: Microscopic Calculations Using a Reversible Charging Process| journal=Biochemistry| volume=25| pages=8368–72| doi=10.1021/bi00374a006|pmid=2435316|issue=26}}</ref><ref name=engg>{{cite journal|author=Lee F S, Chu Z T, Bolger M B, Warshel A|title=Calculations of antibody-antigen interactions: microscopic and semi-microscopic evaluation of the free energies of binding of phosphorylcholine analogs to McPC603|journal=Protein Engg| year=1992| volume=5| issue=3|pages=215–228|doi=10.1093/protein/5.3.215}}</ref>. | |||
| *Performing (1988) the first calculations of the dielectric relaxation of proteins <ref name=suss2>{{cite journal| | |||
| journal=Journal of Molecular Biology| volume=201|Issue=1|year=1988|Pages 139-159| | |||
| doi=10.1016/0022-2836(88)90445-7|title= Evaluation of catalytic free energies in genetically modified proteins|author=Warshel A, Sussman F, Hwang J-K}}</ref>. | |||
| *Introducing (1978) spherical boundary conditions and long-range spherical treatments (1989) <ref name=cpl78></ref> <ref name=kngjcp> {{cite journal|journal=Journal of Chemical Physics|Volume=91|Issue=6| pages=3647| year= 1989|doi=10.1063/1.456845|title=A surface constrained all‐atom solvent model for effective simulations of polar solutions|author=King G, Warshel A}}</ref> <ref name=lrf>{{cite journal|journal=Journal of Chemical Physics|Volume=97|Issue=5|pages=3100| year=1992| doi=10.1063/1.462997|title=A local reaction field method for fast evaluation of long‐range electrostatic interactions in molecular simulations|author=Lee F S, Warshel A}}</ref>. | |||
| *Performing (1991) the first calculations of the dielectric constant of protein active sites (rather than the entire protein) and other selected regions <ref name=jcp91> {{cite journal|journal=Journal of Chemical Physics|Volume=95|Issue=6|pages=4366|year=1991| doi=10.1063/1.461760|title=Microscopic simulations of macroscopic dielectric constants of solvated proteins|author=King G, Lee F S, Warshel A}}</ref> | |||
| === Introducing Simulations of Electron Transfer Processes in Solution and in Proteins === | |||
| Warshel pioneered the simulation of electron transfer processes in the condensed phase <ref name="jpc1982"> {{cite journal|title=Dynamics of reactions in polar solvents. Semiclassical trajectory studies of electron-transfer and proton-transfer reactions|author=Warshel A.|journal=J. Phys. Chem.|year=1982|volume=86|issue=12|pages=2218–2224|doi=10.1021/j100209a016}}</ref>. He developed microscopic free energy functions and introduced the potential energy gap as a generalized reaction coordinate <ref name="jpc1982"> {{cite journal|title=Dynamics of reactions in polar solvents. Semiclassical trajectory studies of electron-transfer and proton-transfer reactions|author=Warshel A.|journal=J. Phys. Chem.|year=1982|volume=86|issue=12|pages=2218–2224|doi=10.1021/j100209a016}}</ref>. His approach provides the microscopic equivalent of Marcus’ theory. He also pioneered the dispersed polaron model, which paved the way for simulations of quantum tunneling in biological systems <ref name=jcphwang> {{cite journal|journal=J. Chem. Phys.| volume=89|issue=2|pages=859| year=1988| doi=10.1063/1.455719|title= Effects of solute–solvent coupling and solvent saturation on solvation dynamics of charge transfer reactions|author=Hwang J-K, Creighton S, King G, Whitney D, Warshel A}} </ref>. Warshel and coworkers presented the first simulation of electron-transfer dynamics in bacterial reaction centers <ref name=crei> {{cite journal| title=Simulating the dynamics of the primary charge separation process in bacterial photosynthesis|author=Creighton S, Hwang J K, Warshel A, Parson W W ,Norris J| journal=Biochemistry| year=1988| volume=27| issue=2| pages=774–781|doi= 10.1021/bi00402a043}}</ref>, and correctly predicted that a three-step mechanism is the actual mechanism <ref name=qrb>{{cite journal|journal=Quarterly Reviews of Biophysics|year=2001|volume=34|pages=563–679|doi=10.1017/S0033583501003730|title=Dynamics of biochemical and biophysical reactions: insight from computer simulations|author=Warshel A, Parson W W}}</ref>. His key advances in this direction include: | |||
| *Introducing (1982) microscopic simulations of electron transfer in solution <ref name="jpc1982"></ref>. | |||
| *Pioneering (1986,1989) the microscopic evaluation of the Marcus free energy functions (and reorganization energies), as well as the simulation of nuclear tunneling effects associated with protein modes <ref name=jcp86hw>{{cite journal| | |||
| journal=Journal of Chemical Physics|Volume=84|Issue=9| year=1986|pages=4938| doi=10.1063/1.449981|title= Simulation of the dynamics of electron transfer reactions in polar solvents: Semiclassical trajectories and dispersed polaron approaches|author=Warshel A, Hwang J-K}}</ref> <ref name=sci89> {{cite journal|journal=Science|year=1989| volume=246| issue=4926| pages=112–116|doi=10.1126/science.2675313|title= Dispersed polaron simulations of electron transfer in photosynthetic reaction centers|author=Warshel A,Chu Z T, Parson W W}}</ref>. | |||
| *Introducing (1989, 1991) the use of MD simulations (dispersed polaron / spin-boson) to study the effect of protein quantized nuclear motions in electron and proton transfer reactions <ref name=sci89></ref><ref name=yadjpc></ref>. | |||
| *Simulating (1988) the primary event in photosynthesis, and predicting a direct hopping mechanism (which was later experimentally confirmed) <ref name=crei></ref><ref name=qrb></ref> | |||
| === Pioneering Simulations of Chemical Reactions in Solution === | |||
| Warshel also pioneered computational methods for the microscopic studies of chemical processes in polar solvents <ref name=cpl78> {{cite journal|journal=Chemical Physics Letters| Volume=55|Issue 3|year=1978|pages=459–465|doi=10.1016/0009-2614(78)84014-7|title=Coupling of charge stabilization, torsion and bond alternation in light-induced reactions of visual pigments|author= Warshel A, Deakyne C}}</ref> <ref name=jpc79>{{cite journal|title=Calculations of chemical processes in solutions|author=Warshel A|journal=J. Phys. Chem.| year=1979| volume=83| issue=12| pages=1640–1652|doi=10.1021/j100475a014}}</ref>. His contributions include the introduction of QM/MM methods to studies of reactions in solution <ref name=cpl78> {{cite journal| journal=Chemical Physics Letters| Volume=55|Issue 3| year=1978| pages=459–465| doi=10.1016/0009-2614(78)84014-7|title=Coupling of charge stabilization, torsion and bond alternation in light-induced reactions of visual pigments|author= Warshel A, Deakyne C}}</ref> <ref name=jpc79>{{cite journal|title=Calculations of chemical processes in solutions|author=Warshel A|journal=J. Phys. Chem.| year=1979| volume=83| issue=12| pages=1640–1652|doi=10.1021/j100475a014}}</ref>. Another major accomplishment was the development of the EVB method <ref name=evb80>{{cite journal|title=An empirical valence bond approach for comparing reactions in solutions and in enzymes|author=Warshel A, Weiss R M|journal= J. Am. Chem. Soc.|year= 1980|volume=102|issue=20|pages=6218–6226|doi= 10.1021/ja00540a008}}</ref> <ref name=evblynn> {{cite journal|title=The empirical valence bond model: theory and applications| author= Kamerlin S C L, Warshel A|year=2011|doi=10.1002/wcms.10|journal= Wiley Interdisciplinary Reviews: Computational Molecular Science|volume=1|issue=1|pages=30–45}}</ref> <ref name=rev93>{{cite journal| title=Simulation of enzyme reactions using valence bond force fields and other hybrid quantum/classical approaches| author= Aqvist J, Warshel A|journal=Chem. Rev.| year=1993| volume=93|issue=7|pages=2523–2544|doi=10.1021/cr00023a010}} </ref> and the introduction of free energy perturbation calculations of activation free energies of reactions in solution <ref name="jpc1982"> {{cite journal|title=Dynamics of reactions in polar solvents. Semiclassical trajectory studies of electron-transfer and proton-transfer reactions|author=Warshel A.|journal=J. Phys. Chem.|year=1982|volume=86|issue=12|pages=2218–2224|doi=10.1021/j100209a016}}</ref> <ref name=simul>{{cite journal|author=Warshel A|year=1984|title=Simulating the Energetics and Dynamics of Enzymatic Reactions|journal=Pontificiae Academiae Scientiarum Scripta Varia| volume=55|pages=60}}</ref>. These methods led to the first microscopic calculations of the dynamics and energetics of charge transfer reactions in polar solvents and in enzymes . The EVB approach has become widely used in many applications, including in enzyme design <ref name=chemrev> {{cite journal|title=Electrostatic Basis for Enzyme Catalysis|author=Warshel A, Sharma P K, Kato M, Xiang Y, Liu H, Olsson M H M|journal=Chemical Reviews| year=2006| volume=106| issue=8| pages=3210–3235|doi=10.1021/cr0503106| pmid=16895325}}</ref> <ref name =mar10>{{cite journal|doi= 10.1073/pnas.1010381107| year=2010|volume=107|isue=39|pages=16869–16874|journal = Proc Natl Acad Sci USA|title=Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase|author=Frushicheva M P, Cao J, Chu Z T, Warshel A}}</ref>. His key advances in this direction include: | |||
| *Introducing (1978) calculations of solvent effects on chemical reactions, using realistic yet simplified solvent models <ref name=cpl78></ref><ref name=jpc79></ref>. | |||
| *Performing (1982) the first MD simulations of proton transfer reactions in solution <ref name="jpc1982"></ref>. | |||
| *Introducing (1982) the energy gap as the reaction coordinate for studies of reactions in solution and in proteins <ref name="jpc1982"></ref>. | |||
| *Introducing (1980, 1988) the EVB as a general tool for simulating condensed-phase reactions) <ref name=evb80></ref> <ref name=jcphwang></ref>. | |||
| *Introducing (1986) MD simulations of quantum mechanical nuclear tunneling in electron transfer reactions <ref name=jcp86hw></ref> | |||
| === Laying the Basis for Modern Force Fields === | |||
| In 1967, Warshel realized the great advantages of programming molecular force fields using a Cartesian coordinate representation rather than in internal coordinates as was the norm at the time. His approach <ref name=cons1>{{cite journal |author=Lifson S, Warshel A.|year= 1968| title=A Consistent Force Field for Calculation on Conformations, Vibrational Spectra and Enthalpies of Cycloalkanes and n-Alkane Molecules| journal = J. Phys. Chem.| volume=49| pages=5116| doi=10.1063/1.1670007 |issue=11}}</ref><ref name=cons2>{{cite journal |author=Warshel A, Lifson S.|year=1970| title=Consistent Force Field Calculations. II. Crystal Structure, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations and Enthalpies of Alkanes| journal= J. Chem. Phys.| volume=53| pages=582| doi=10.1063/1.1674031 |issue=2}}</ref> enormously simplified the evaluation of analytic derivatives, allowing one to generate large molecules and evaluate the normal modes of large molecules. This was a key factor in the development of the Consistent Force Field (CFF) computer program <ref name=lev01> {{cite journal|author=Levitt, M|year=2001|title=The birth of computational structural biology|journal=Nat. Struct. Biol.|volume=8|pages=392–393|doi=10.1038/87545|pmid=11323711}}</ref> (in cooperation with M. Levitt and S. Lifson). The CFF program has provided the basis for many features of most of the current macromolecular modeling programs (e.g. CHARMM, AMBER, BIOGRAPH, DISCOVER and GROMOS). He also introduced polarizable force fields <ref name="warshel">{{cite journal| author=Warshel A, Levitt M| year=1976| title=Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme| journal=J. Mol. Biol.| volume=103| pages=227–49| doi=10.1016/0022-2836(76)90311-9| pmid=985660| issue=2}}</ref> and the consistent reactive force field <ref name=evb80>{{cite journal|title=An empirical valence bond approach for comparing reactions in solutions and in enzymes|author=Warshel A, Weiss R M|journal= J. Am. Chem. Soc.|year= 1980|volume=102|issue=20|pages=6218–6226|doi= 10.1021/ja00540a008}}</ref> (namely the EVB). His key advances in this direction include: | |||
| *Introducing (1968) the crucial idea of using Cartesian coordinates in general force field programs <ref name=cons1></ref><ref name=cons1></ref>. | |||
| *Introducing (1968) vibrational calculations and consistent force field parameterization in molecular mechanics <ref name=cons1></ref><ref name=cons1></ref>. | |||
| *Co-developing (1969) the program that is the basis of all current molecular simulation programs (1969) . | |||
| *Pioneering (1976) polarizable force fields <ref name="warshel"></ref>. | |||
| *Pioneering (1980) the Empirical Valence Bond <ref name=evb80></ref>. | |||
| ==References== | ==References== | ||
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| Arieh Warshel | |
|---|---|
 | |
| Born | (1940-11-20) November 20, 1940 (age 84) Kibbutz Sde-Nahum, Israel |
| Nationality | Israeli, American |
| Citizenship | Israel, United States |
| Alma mater | Technion, Weizmann Institute |
| Known for | computational enzymology, electrostatics, enzyme catalysis |
| Scientific career | |
| Fields | Chemistry, Biochemistry, Biophysics |
| Institutions | University of Southern California, Weizmann Institute, MRC Laboratory of Molecular Biology |
Arieh Warshel is a Distinguished Professor of Chemistry and Biochemistry at the University of Southern California. He is known for his work on computational biochemistry and biophysics, and, in particular, for having pioneered computer simulations of the function of biological systems, and for developing what is now known as Computational Enzymology.
Arieh Warshel was born in Kibbutz Sde-Nahum in Israel in 1940. After serving in the Israeli Army (final rank Captain), he attended the Technion in Haifa, where he received his BSc degree in Chemistry, Summa Cum Laude, in 1966. He subsequently earned both MSc and PhD degrees in Chemical Physics (1967 and 1969 respectively) from the Weizmann Institute of Science, together with Shneior Lifson. After his PhD, he did postdoctoral work at Harvard University. From 1972 to 1976, he was at the Weizmann Institute and at the MRC Laboratory for Molecular Biology in Cambridge, England. In 1976, he joined the faculty of the Department of Chemistry at USC, where he is a Distinguished Professor of Chemistry and Biochemistry.
Warshel has been elected a member of the United States National Academy of Sciences, a fellow of the Royal Society of Chemistry (FRSC), and a fellow of the Biophysical Society (2000). He was additionally awarded the Technion Award for best third-year student in Chemistry (1965), the Mifal-Hapays Prize (1969), the Alfred P. Sloan Fellowship (1978-1980), the USC Associated Award for Creativity in Research (1981), the 1993 Annual Award of the International Society of Quantum Biology and Pharmacology, the Tolman Medal (2003), and the 2006 President’s Award for Computational Biology from the ISQBP.
Research Achievements
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Warshel has made major contributions in introducing computational methods for studying structure-function correlation in biological molecules. He pioneered (and co-pioneered) simulation software, as well as key methods and concepts for microscopic studies of the functional properties of biological molecules, including the Cartesian-based force field program CFF , the QM/MM method for simulating enzymatic reactions, , molecular dynamics simulations of biological molecules , microscopic electrostatic models for proteins , free energy perturbations in proteins , and other key advances. Further information can be found at Warshel's group website.
References
- "The University of Southern California Distinguished Professors". Archived from the original on 26 February 2011. Retrieved 2011-01-24.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - "Arieh Warshel Elected to the National Academy of Sciences". Retrieved 2011-03-31.
- "Arieh Warshel Elected to Royal Society of Chemistry". Retrieved 2011-03-31.
- Lifson S, Warshel A. (1968). "A Consistent Force Field for Calculation on Conformations, Vibrational Spectra and Enthalpies of Cycloalkanes and n-Alkane Molecules". J. Phys. Chem. 49 (11): 5116. doi:10.1063/1.1670007.
- Warshel A, Lifson S. (1970). "Consistent Force Field Calculations. II. Crystal Structure, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations and Enthalpies of Alkanes". J. Chem. Phys. 53 (2): 582. doi:10.1063/1.1674031.
- Levitt, M (2001). "The birth of computational structural biology". Nat. Struct. Biol. 8: 392–393. doi:10.1038/87545. PMID 11323711.
- ^ Warshel A, Levitt M (1976). "Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme". J. Mol. Biol. 103 (2): 227–49. doi:10.1016/0022-2836(76)90311-9. PMID 985660.
- Warshel A. (1976). "Bicycle-pedal Model for the First Step in the Vision Process". Nature. 260 (5553): 679–83. doi:10.1038/260679a0. PMID 1264239.
- Warshel A. (2002). "Molecular Dynamics Simulations of Biological Reactions". Acc. Chem. Res. 35 (6): 385–395. doi:10.1021/ar010033z. PMID 12069623.
- Warshel A, Russell S T. (1984). "Calculations of Electrostatic Interactions in Biological Systems and in Solutions". Quart. Rev. Biophys. 17 (3): 283. doi:10.1017/S0033583500005333.
- Warshel A (1984). "Simulating the Energetics and Dynamics of Enzymatic Reactions". Pontificiae Academiae Scientiarum Scripta Varia. 55: 60.