Improved side-chain torsion potentials for the Amber ff99SB protein force field.
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.
Lindorff-Larsen
Kresten
K
D. E. Shaw Research, New York, New York 10036, USA.
Piana
Stefano
S
Palmo
Kim
K
Maragakis
Paul
P
Klepeis
John L
JL
Dror
Ron O
RO
Shaw
David E
DE
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
D000596:Amino Acids; D010455:Peptides; D011506:Proteins
Adv Protein Chem. 2005;72:79-104
16581373
J Biomol NMR. 2005 Mar;31(3):201-16
15803394
J Comput Chem. 2004 Aug;25(11):1400-15
15185334
J Am Chem Soc. 2001 Jul 25;123(29):7081-93
11459487
J Chem Phys. 2007 Jan 28;126(4):046101
17286520
J Comput Chem. 1986 Apr;7(2):230-252
29160584
Proteins. 2006 Nov 15;65(3):712-25
16981200
J Mol Biol. 1992 Oct 5;227(3):757-75
1383552
Nature. 2005 Jan 13;433(7022):128-32
15650731
Curr Opin Struct Biol. 2008 Apr;18(2):134-9
18215513
Biophys J. 2008 May 15;94(10):L75-7
18339748
J Am Chem Soc. 2003 Jul 23;125(29):8959-66
12862493
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10901-6
16829580
J Chem Phys. 2004 May 22;120(20):9665-78
15267980
Biochemistry. 1991 Jan 29;30(4):986-96
1989688
Nat Struct Biol. 2000 Nov;7 Suppl:957-9
11103999
Biophys J. 2007 Jun 1;92(11):3817-29
17351000
Protein Sci. 2001 Apr;10(4):677-88
11274458
Proteins. 2000 Aug 15;40(3):389-408
10861930
Proc Natl Acad Sci U S A. 2004 May 4;101(18):6946-51
15118103
Curr Opin Struct Biol. 2009 Apr;19(2):120-7
19361980
Biophys J. 2008 Jul;95(1):L07-9
18456823
J Biomol NMR. 2004 Nov;30(3):327-46
15754058
Protein Sci. 2003 Dec;12(12):2719-31
14627733