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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

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. His contributions include the following:

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 . Performing (1976) the first molecular dynamics (MD) simulation of a biological process . Co-introducing the simplified protein-folding model (1975) . 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 . Performing (1984) the first free-energy perturbation calculations in proteins . Introducing (1986) consistent structure-based calculations of the redox potentials of proteins . Introducing (1991) simulations of quantum-mechanical tunneling in enzymatic reactions and in solution . Introducing (1992) microscopic linear response approximation (LRA) calculations of absolute binding free energies . Introducing (1999) simulations of time-dependent proton transport in proteins .

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 . 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 . 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 . Proposing (1978) and demonstrating that polar preorganization is the key factor in enzyme catalysis, and rationalizing the inverted catalysis/stability relationship . Pioneering free energy perturbation (1984) calculations of enzymatic reactions, which were subsequently extended to the reactivity of many key enzyme families . Performing (1984) the first simulation of dynamical contributions to enzyme catalysis. Quantifying (2000) entropic contributions to enzyme catalysis . Systematically simulating (1980-2011 ) almost all of the available catalytic proposals, and demonstrating that most enzymes catalyze their reactions by electrostatic effects .

Pioneering MD Simulations of Biological Functions

The first use of MD in studying a biological process was presented by Warshel in 1976 . His simulations of the primary event in the vision process correctly predicted the photoisomerization time of rhodopsin. This prediction has been subsequently experimentally confirmed . Warshel also used the same semiclassical approach in pioneering simulations of the primary electron transfer in photosynthesis . Warshel’s 1976 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., . 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 . The predicted time has been since confirmed experimentally 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 . Demonstrating (1984) that productive trajectories in enzymatic reactions take about 1ps . 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 . He also introduced the first simplified microscopic treatment of the energy of charges in solvated proteins and the first free energy perturbation study of a charge in a protein . His models opened the way to realistic calculations of pKas, redox potentials and absolute binding free energies in proteins. His key advances in this direction include:

Introducting (1976) consistent microscopic models of solvated proteins . Establishing (1978) the key role of the polarity of protein active sites . Establishing (1984) the desolvation penalty and the crucial compensation effects of the protein permanent dipoles, and quantifying the energetics of ion pairs in proteins . Introducing (1986) free energy perturbation and LRA calculations (1992) of electrostatic energies in proteins . Performing (1988) the first calculations of the dielectric relaxation of proteins . Introducing (1978) spherical boundary conditions and long-range spherical treatments (1989) . Performing (1991) the first calculations of the dielectric constant of protein active sites (rather than the entire protein) and other selected regions

Introducing Simulations of Electron Transfer Processes in Solution and in Proteins

Warshel pioneered the simulation of electron transfer processes in the condensed phase . He developed microscopic free energy functions and introduced the potential energy gap as a generalized reaction coordinate . 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 . Warshel and coworkers presented the first simulation of electron-transfer dynamics in bacterial reaction centers , and correctly predicted that a three-step mechanism is the actual mechanism . His key advances in this direction include:

Introducing (1982) microscopic simulations of electron transfer in solution . 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 . 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 . Simulating (1988) the primary event in photosynthesis, and predicting a direct hopping mechanism (which was later experimentally confirmed)

Pioneering Simulations of Chemical Reactions in Solution

Warshel also pioneered computational methods for the microscopic studies of chemical processes in polar solvents . His contributions include the introduction of QM/MM methods to studies of reactions in solution . Another major accomplishment was the development of the EVB method and the introduction of free energy perturbation calculations of activation free energies of reactions in solution . 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 . His key advances in this direction include:

Introducing (1978) calculations of solvent effects on chemical reactions, using realistic yet simplified solvent models . Performing (1982) the first MD simulations of proton transfer reactions in solution . Introducing (1982) the energy gap as the reaction coordinate for studies of reactions in solution and in proteins . Introducing (1980, 1988) the EVB as a general tool for simulating condensed-phase reactions) . Introducing (1986) MD simulations of quantum mechanical nuclear tunneling in electron transfer reactions .

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 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 (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 and the consistent reactive force field (namely the EVB). His key advances in this direction include:

Introducing (1968) the crucial idea of using Cartesian coordinates in general force field programs . Introducing (1968) vibrational calculations and consistent force field parameterization in molecular mechanics . Co-developing (1969) the program that is the basis of all current molecular simulation programs (1969) . Pioneering (1976) polarizable force fields . Pioneering (1980) the Empirical Valence Bond .

References

1. "The University of Southern California Distinguished Professors". Retrieved 2011-01-24.
2. "Arieh Warshel Elected to the National Academy of Sciences". Retrieved 2011-03-31.
3. "Arieh Warshel Elected to Royal Society of Chemistry". Retrieved 2011-03-31.
4. ^ 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.
5. ^ 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.
6. ^ Levitt, M (2001). "The birth of computational structural biology". Nat. Struct. Biol. 8: 392–393. doi:10.1038/87545.
7. ^ 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.
8. ^ 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.
9. ^ Warshel A. (2002). "Molecular Dynamics Simulations of Biological Reactions". Acc. Chem. Res. 35 (6): 385–395. doi:10.1021/ar010033z. PMID 12069623.
10. ^ 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.
11. ^ Warshel A (1984). "Simulating the Energetics and Dynamics of Enzymatic Reactions". Pontificiae Academiae Scientiarum Scripta Varia. 55: 60.
12. Levitt M, Warshel A. (1975). "Computer Simulations of Protein Folding". Nature. 253 (5494): 694–8. doi:10.1038/253694a0. PMID 1167625.
13. Warshel A (1981). "Calculations of Enzymic Reactions: Calculations of pKa, Proton Transfer Reactions, and General Acid Catalysis Reactions in Enzymes". Biochemistry. 20 (11): 3167–77. doi:10.1021/bi00514a028. PMID 7248277.
14. Churg, A K, Warshel A (1986). "Control of the redox potential of cytochrome and microscopic dielectric effects in proteins". Biochemistry. 25 (7): 1675–1681. doi:10.1021/bi00355a035.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. ^ Hwang J K, Chu Z T, Yadav A, Warshel A (1991). "Simulations of quantum mechanical corrections for rate constants of hydride-transfer reactions in enzymes and solutions". J Phys Chem. 95 (22): 8445–8448. doi:10.1021/j100175a009.{{cite journal}}: CS1 maint: multiple names: authors list (link)
16. ^ Lee F S, Chu Z T, Bolger M B, Warshel A (1992). "Calculations of antibody-antigen interactions: microscopic and semi-microscopic evaluation of the free energies of binding of phosphorylcholine analogs to McPC603". Protein Engg. 5 (3): 215–228. doi:10.1093/protein/5.3.215.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "engg" was defined multiple times with different content (see the help page).
17. Sham Y Y, Muegge I, Warshel A (1999). "Simulating proton translocations in proteins: Probing proton transfer pathways in the Rhodobacter sphaeroides reaction center". Proteins: Structure, Function, and Bioinformatics. 36 (4): 484–500. doi:10.1002/(SICI)1097-0134(19990901)36:4<484::AID-PROT13>3.0.CO;2-R.{{cite journal}}: CS1 maint: multiple names: authors list (link)
18. Olsson M H M, Warshel A (2006). "Monte Carlo simulations of proton pumps: On the working principles of the biological valve that controls proton pumping in cytochrome c oxidase". Proc Natl Acad Sci USA. 103 (17): 6500–6505. doi:10.1073/pnas.0510860103.
19. ^ Warshel A (1978). "Energetics of enzyme catalysis". Proc. Natl. Acad. Sci. USA. 75 (11): 5250–4. doi:10.1073/pnas.75.11.5250. PMC 392938. PMID 281676.
20. ^ Warshel A, Sharma P K, Kato M, Xiang Y, Liu H, Olsson M H M (2006). "Electrostatic Basis for Enzyme Catalysis". Chemical Reviews. 106 (8): 3210–3235. doi:10.1021/cr0503106.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "chemrev" was defined multiple times with different content (see the help page).
21. Villà J, Štrajbl M,Glennon T M,Sham Y Y,Chu Z T, Warshel A (2000). "How important are entropic contributions to enzyme catalysis?". 97 (22): 11899–11904. doi:10.1073/pnas.97.22.11899. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
22. Warshel A (1991). Computer Simulation of Chemical Reactions in Enzymes and Solutions. New York: John Wiley & Sons.
23. ^ Wang Q, Schoenlein R W, Peteanu L A, Mathies R A, Shank C V (1994). "Vibrationally coherent photochemistry in the femtosecond primary event of vision". Science (5184): 422–424. doi:10.1126/science.7939680. {{cite journal}}: Unknown parameter |Volume= ignored (|volume= suggested) (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "mathis" was defined multiple times with different content (see the help page).
24. Arnaud C (2010). "Probing Key Vision Event". Chemical and Engineering News: 11. {{cite journal}}: Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)
25. ^ Creighton S, Hwang J K, Warshel A, Parson W W ,Norris J (1988). "Simulating the dynamics of the primary charge separation process in bacterial photosynthesis". Biochemistry. 27 (2): 774–781. doi:10.1021/bi00402a043.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "crei" was defined multiple times with different content (see the help page).
26. "Nature of the Surface Crossing Process in Bacteriorhodopsin:  Computer Simulations of the Quantum Dynamics of the Primary Photochemical Event". J Phys Chem B (40): 9857–9871. 2001. doi:10.1021/jp010704a. {{cite journal}}: Unknown parameter |authors= ignored (help); Unknown parameter |vol= ignored (|volume= suggested) (help)
27. ^ Frutos L M, Andruniów T, Santoro F,Ferré N, Olivucci M. (2007). "Tracking the excited-state time evolution of the visual pigment with multiconfigurational quantum chemistry". Proc Natl Acad Sci USA. 104 (19): 7764–7769. doi:10.1073/pnas.0701732104.{{cite journal}}: CS1 maint: multiple names: authors list (link)
28. Warshel A (1984). "Dynamics of Enzymatic Reactions". Proc. Natl. Acad. Sci.USA. 81 (2): 444–448. doi:10.1073/pnas.81.2.444.
29. ^ Warshel A, Sussman F, King G. (1986). "Free Energy of Charges in Solvated Proteins: Microscopic Calculations Using a Reversible Charging Process". Biochemistry. 25 (26): 8368–72. doi:10.1021/bi00374a006. PMID 2435316.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "suss" was defined multiple times with different content (see the help page).
30. ^ Warshel A, Sharma P K, Kato M, Parson W W. (2006). "Modeling Electrostatic Effects in Proteins". Biochim. Biophys. Acta. 1764 (11): 1647–1676. doi:10.1016/j.bbapap.2006.08.007. PMID 17049320.{{cite journal}}: CS1 maint: multiple names: authors list (link)
31. Warshel A, Sussman F, Hwang J-K (1988). "Evaluation of catalytic free energies in genetically modified proteins". Journal of Molecular Biology. doi:10.1016/0022-2836(88)90445-7. {{cite journal}}: Text "Pages 139-159" ignored (help); Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)CS1 maint: multiple names: authors list (link)
32. ^ Warshel A, Deakyne C (1978). "Coupling of charge stabilization, torsion and bond alternation in light-induced reactions of visual pigments". Chemical Physics Letters. doi:10.1016/0009-2614(78)84014-7. {{cite journal}}: Text "Issue 3" ignored (help); Unknown parameter |Pages= ignored (|pages= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help) Cite error: The named reference "cpl78" was defined multiple times with different content (see the help page).
33. King G, Warshel A (1989). "A surface constrained all‐atom solvent model for effective simulations of polar solutions". Journal of Chemical Physics: 3647. doi:10.1063/1.456845. {{cite journal}}: Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)
34. Lee F S, Warshel A (1992). "A local reaction field method for fast evaluation of long‐range electrostatic interactions in molecular simulations". Journal of Chemical Physics: 3100. doi:10.1063/1.462997. {{cite journal}}: Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)
35. King G, Lee F S, Warshel A (1991). "Microscopic simulations of macroscopic dielectric constants of solvated proteins". Journal of Chemical Physics: 4366. doi:10.1063/1.461760. {{cite journal}}: Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)CS1 maint: multiple names: authors list (link)
36. ^ Warshel A. (1982). "Dynamics of reactions in polar solvents. Semiclassical trajectory studies of electron-transfer and proton-transfer reactions". J. Phys. Chem. 86 (12): 2218–2224. doi:10.1021/j100209a016.
37. ^ Hwang J-K, Creighton S, King G, Whitney D, Warshel A (1988). "Effects of solute–solvent coupling and solvent saturation on solvation dynamics of charge transfer reactions". J. Chem. Phys. 89 (2): 859. doi:10.1063/1.455719.{{cite journal}}: CS1 maint: multiple names: authors list (link)
38. ^ Warshel A, Parson W W (2001). "Dynamics of biochemical and biophysical reactions: insight from computer simulations". Quarterly Reviews of Biophysics. 34: 563–679. doi:10.1017/S0033583501003730.
39. ^ Warshel A, Hwang J-K (1986). "Simulation of the dynamics of electron transfer reactions in polar solvents: Semiclassical trajectories and dispersed polaron approaches". Journal of Chemical Physics: 4938. doi:10.1063/1.449981. {{cite journal}}: Unknown parameter |Issue= ignored (|issue= suggested) (help); Unknown parameter |Volume= ignored (|volume= suggested) (help)
40. ^ Warshel A,Chu Z T, Parson W W (1989). "Dispersed polaron simulations of electron transfer in photosynthetic reaction centers". Science (4926): 112–116. doi:10.1126/science.2675313. {{cite journal}}: Unknown parameter |Vol= ignored (|volume= suggested) (help)CS1 maint: multiple names: authors list (link)
41. ^ Warshel A (1979). "Calculations of chemical processes in solutions". J. Phys. Chem. 83 (12): 1640–1652. doi:10.1021/j100475a014.
42. ^ Warshel A, Weiss R M (1980). "An empirical valence bond approach for comparing reactions in solutions and in enzymes". J. Am. Chem. Soc. 102 (20): 6218–6226. doi:10.1021/ja00540a008.
43. Kamerlin S C L, Warshel A (2011). "The empirical valence bond model: theory and applications". Wiley Interdisciplinary Reviews: Computational Molecular Science. 1 (1): 30–45. doi:10.1002/wcms.10.
44. Aqvist J, Warshel A (1993). "Simulation of enzyme reactions using valence bond force fields and other hybrid quantum/classical approaches". Chem. Rev. 93 (7): 2523–2544. doi:10.1021/cr00023a010.
45. Frushicheva M P, Cao J, Chu Z T, Warshel A (2010). "Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase". Proc Natl Acad Sci USA. 107: 16869–16874. doi:10.1073/pnas.1010381107. {{cite journal}}: Unknown parameter |isue= ignored (help)CS1 maint: multiple names: authors list (link)

External links

• Warshel research group at the University of Southern California
• Warshel's faculty website at USC

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