title: Improved side-chain torsion potentials for the Amber ff99SB protein force field.
abstract: Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data.
authors.affiliation: D. E. Shaw Research, New York, New York 10036, USA.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.forename: Stefano
authors.initials: S
authors.lastname: Piana
authors.forename: Kim
authors.initials: K
authors.lastname: Palmo
authors.forename: Paul
authors.initials: P
authors.lastname: Maragakis
authors.forename: John L
authors.initials: JL
authors.lastname: Klepeis
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002645:Chickens; D030562:Databases, Protein; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D015203:Reproducibility of Results; D013816:Thermodynamics; D054159:Torsion, Mechanical
chemical_list: D000596:Amino Acids; D010455:Peptides; D011506:Proteins
references.citation: Adv Protein Chem. 2005;72:79-104
references.pmid: 16581373
references.citation: J Biomol NMR. 2005 Mar;31(3):201-16
references.pmid: 15803394
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: J Am Chem Soc. 2001 Jul 25;123(29):7081-93
references.pmid: 11459487
references.citation: J Chem Phys. 2007 Jan 28;126(4):046101
references.pmid: 17286520
references.citation: J Comput Chem. 1986 Apr;7(2):230-252
references.pmid: 29160584
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: J Mol Biol. 1992 Oct 5;227(3):757-75
references.pmid: 1383552
references.citation: Nature. 2005 Jan 13;433(7022):128-32
references.pmid: 15650731
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):134-9
references.pmid: 18215513
references.citation: Biophys J. 2008 May 15;94(10):L75-7
references.pmid: 18339748
references.citation: J Am Chem Soc. 2003 Jul 23;125(29):8959-66
references.pmid: 12862493
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10901-6
references.pmid: 16829580
references.citation: J Chem Phys. 2004 May 22;120(20):9665-78
references.pmid: 15267980
references.citation: Biochemistry. 1991 Jan 29;30(4):986-96
references.pmid: 1989688
references.citation: Nat Struct Biol. 2000 Nov;7 Suppl:957-9
references.pmid: 11103999
references.citation: Biophys J. 2007 Jun 1;92(11):3817-29
references.pmid: 17351000
references.citation: Protein Sci. 2001 Apr;10(4):677-88
references.pmid: 11274458
references.citation: Proteins. 2000 Aug 15;40(3):389-408
references.pmid: 10861930
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6946-51
references.pmid: 15118103
references.citation: Curr Opin Struct Biol. 2009 Apr;19(2):120-7
references.pmid: 19361980
references.citation: Biophys J. 2008 Jul;95(1):L07-9
references.pmid: 18456823
references.citation: J Biomol NMR. 2004 Nov;30(3):327-46
references.pmid: 15754058
references.citation: Protein Sci. 2003 Dec;12(12):2719-31
references.pmid: 14627733