title: A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations.
abstract: Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA. yduan@udel.edu
authors.forename: Yong
authors.initials: Y
authors.lastname: Duan
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Shibasish
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Lee
authors.forename: Guoming
authors.initials: G
authors.lastname: Xiong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.forename: Ray
authors.initials: R
authors.lastname: Luo
authors.forename: Taisung
authors.initials: T
authors.lastname: Lee
authors.forename: James
authors.initials: J
authors.lastname: Caldwell
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Kollman
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D016208:Databases, Factual; D004151:Dipeptides / Q000737:chemistry; D006860:Hydrogen Bonding; D008432:Mathematical Computing; D008962:Models, Theoretical; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D010455:Peptides; D011506:Proteins; D012997:Solvents; D014867:Water