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.

Comparison of multiple Amber force fields and development of improved protein backbone parameters

“…In this case, the root mean square difference, absolute average error and maximum error are 1.31, 1.05 and 3.43 kcal/mol. This is comparable to similar fitting errors obtained in ff99 11 and ff03 24 . For comparison, the values of backbone dihedral parameters for many other variants of AMBER force field are given in the supplementary information (Table S4).…”

“…All molecular dynamics simulations for Gly 3 and Ala 3 tetrapeptides were carried out with the sander module in AMBER8 7 using several different force fields as discussed in the main text: ff94 5 , ff99 11 , Garcia's modification of ff94 13 with C-N-C α -C and N-C α -C-N terms zeroed (denoted ff94gs in the text), Pande's modified ff99 19 with C-N-C α -C term replaced by the one from ff94 (denoted ff99ϕ), ff03 24 (as present in AMBER8 distribution) and ff99SB developed as described above. The time step was 2 fs, and all bonds involving hydrogen were constrained by SHAKE with a tolerance of 10 −4 Å. Glycine and alanine tetrapeptide systems were solvated by approximately 520 TIP3P 33 water molecules in a periodic box.…”

“…The correspondence of the distributions obtained from PDB and simulations has been used extensively in force field validation and development 21,[24][25][26] . This is the basis for our first test and qualitatively evaluates our dihedral parameter set.…”

“…A different approach was taken by Duan et al 24 , who recently introduced a more extensive modification of ff94/ff99 (called ff03), in which a fundamentally different concept to derivation of partial atomic charges was used. Instead of relying on the HF/6-31G* approach to provide aqueous-phase charges, a low-dielectric continuum model corresponding to an organic solvent environment was included directly in the QM calculation of the dihedral parameters and electrostatic potential (from which the charges are obtained).…”

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

“…[47,48] Protein coordinates were prepared starting from a crystal structure of human 17β-HSD1 in complex with estradiol and NADP + (PDB ID: 1FDT). [49] After removal of ligand atoms, a grid box of approximately 7.5 nm³ was set up around the active site of the enzyme.…”