Development of a new physics-based internal coordinate mechanics force field and its application to protein loop modeling

被引:57
作者
Arnautova, Yelena A. [1 ]
Abagyan, Ruben A. [1 ]
Totrov, Maxim [1 ]
机构
[1] Molsoft LLC, La Jolla, CA 92037 USA
关键词
loop modeling; conformational search; all-atom force field; implicit solvent; molecular mechanics; ICM; MOLECULAR-DYNAMICS SIMULATIONS; STRUCTURALLY VARIABLE REGIONS; CRYSTAL-STRUCTURE PREDICTION; CONFORMATIONAL FREE-ENERGIES; AB-INITIO CONSTRUCTION; RING-LIKE STRUCTURES; EVEN N-ALKANES; ORGANIC-MOLECULES; SURFACE LOOPS; MONTE-CARLO;
D O I
10.1002/prot.22896
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report the development of internal coordinate mechanics force field (ICMFF), new force field parameterized using a combination of experimental data for crystals of small molecules and quantum mechanics calculations. The main features of ICMFF include: (a) parameterization for the dielectric constant relevant to the condensed state (epsilon = 2) instead of vacuum, (b) an improved description of hydrogen-bond interactions using duplicate sets of van der Waals parameters for heavy atom-hydrogen interactions, and (c) improved backbone covalent geometry and energetics achieved using novel backbone torsional potentials and inclusion of the bond angles at the C-alpha atoms into the internal variable set. The performance of ICMFF was evaluated through loop modeling simulations for 4-13 residue loops. ICMFF was combined with a solvent-accessible surface area solvation model optimized using a large set of loop decoys. Conformational sampling was carried out using the biased probability Monte Carlo method. Average/median backbone root-mean-square deviations of the lowest energy conformations from the native structures were 0.25/0.21 angstrom for four residues loops, 0.84/0.46 A for eight residue loops, and 1.16/0.73 angstrom for 12 residue loops. To our knowledge, these results are significantly better than or comparable with those reported to date for any loop modeling method that does not take crystal packing into account. Moreover, the accuracy of our method is on par with the best previously reported results obtained considering the crystal environment. We attribute this success to the high accuracy of the new ICM force field achieved by meticulous parameterization, to the optimized solvent model, and the efficiency of the search method. Proteins 2011; 79:477-498. (C) 2010 Wiley-Liss, Inc.
引用
收藏
页码:477 / 498
页数:22
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