Refining the description of peptide backbone conformations improves protein simulations using the GROMOS 53A6 force field

Abstract

The GROMOS 53A6 parameter sets have been shown to reproduce an extensive range of thermodynamics data in condensed phase (Oostenbrink et al., J Comput Chem 2004, 25, 1656), mainly due to the reoptimized nonbonded interactions. Here, we derive refinements for the descriptions of peptide backbone conformations for this parameter set. A two-dimensional adaptive umbrella sampling procedure was employed to determine the free energy surfaces of model alanine and glycine dipeptides in solution to high accuracy, with sampling errors below 0.8 kJ mol(-1) for relative free energies between major minima. Comparisons of these surfaces with quantum mechanical ones and conformation distributions in protein crystal structures indicated that refined treatments of backbone torsional angle terms are necessary. The high accuracy of the computed free energy surfaces allowed us to consider two types of corrections, one numerically and exactly reproducing the quantum mechanical results, and the other using small analytical terms to correct major deficiencies for the dipeptide systems. In addition, aiming at improving the directionality of backbone-backbone hydrogen bonds, we optimized and tested an off-center charge model for the peptide backbone carbonyl oxygen. Extensive molecular dynamics simulations of five proteins and two peptides in solution indicate that refined treatments of backbone dihedral angles lead to substantial improvements of the simulations. Being much simpler, the analytical terms perform as good as or even slightly better than the exact numerical corrections. Although using off-center charges brought some improvements, the directionality of hydrogen bonds have not been significantly improved.

Definition and testing of the GROMOS force-field versions 54A7 and 54B7

“…Each system was first energy minimised in vacuo, then the protein plus RNA molecules in the case of FOX were solvated in cubic boxes filled with simple point charge (SPC) water (Berendsen et al 1981) molecules. Periodic Table 1 Force-field parameters of the dihedral-angle term for peptide backbone u-and w-torsional angles in the GROMOS force field Oostenbrink et al (2004) and from Cao et al (2009) Term 45A4 and 53A6 (Oostenbrink et al 2004) 54A7 Liu (Cao et al 2009)…”

“…All simulations were performed using a modified version of the GROMOS biomolecular simulation software (Christen et al 2005) in conjunction with the parameter set of the GROMOS force field indicated: 45A4 (Schuler et al 2001), 53A6 (Oostenbrink et al 2004), Liu (Cao et al 2009) or 54A7. Note that the CM system was not simulated using the Liu modification.…”

“…Subsequently, a variety of torsional-angle potential energy functions were investigated by different workers. Cao et al (2009) proposed a correction where the u=w torsional angle terms were reparametrised and a torsional cross term depending on the sum of the u-and w-angles was added. In an alternative approach leading to the 54A7 force field, the torsional angle terms were reparametrised based on fitting to a large set of highresolution crystal structures (Xu et al in preparation) and the N-O non-bonded interactions between the peptide nitrogen and oxygen atoms was adjusted to be less repulsive.…”

Exploration of the chlorpyrifos escape pathway from acylpeptide hydrolases using steered molecular dynamics simulations

“…For the ligands, the Dundee PRODRG (Schüttelkopf & van Aalten, 2004) server was used to build a Gromacs topology for chlorpyrifos, and the .itp file containing the molecular information was obtained. We added the .itp file to the protein .top file, and then the protein-ligands complex simulations were again carried out using the GROMOS force field force parameter set 53A6 (Cao, Lin, Wang, & Liu, 2009). To keep each system in an electrically neutral state, the appropriate number of sodium ions was added to randomly replace the water molecules.…”

Structural character of α-syn12 peptide in solution via temperature replica exchange molecular dynamics simulations

“…The results indicated that there existed systematic biases in the description of protein local conformations by widely-used molecular mechanics force fields. [14] Efforts have been made to refme the treatments of protein backbone conformations in empirical force fields including CHARMM, [15] AMBER, [16] GROMOS, [17] and OPLS-AA.…”