A Coupled Main Chain Torsional Potential For Protein Dynamics And Explicit Polarization Effect On Protein Crystal Modeling

The accuracy of force fields is of the utmost importance in molecular modeling of proteins. Despite of successful applications of force fields for decades, some inherent flaws in force fields, like improper secondary propensities and fixed atomic charges, which sometimes lead improbable results, are exposed in different aspects of bio-molecular research. Hence, a correction to current force fields is desirable.Recently, we refit main chain torsion based AMBER03and AMBER99SB force fields. We choose alanine dipeptide as the study model. Main chain torsions of alanine dipeptide are parameterized into coupled2-dimensional Fourier expansions based on quantum mechanical (QM) calculations at M06-2X/aug-cc-pvtz//HF/6-31G**level. Solvation effect is considered by employing polarizable continuum model at the first parameter and employing SMD model based on solute electron density. Utilization of the M06-2X functional leads to precise potential energy surface that is comparable to or even better than MP2level, but with much less computational demand. Parameterization of the2D expansions is against the full main chain torsion space instead of just a few low energy conformations. This procedure is similar to that for the development of AMBER03force field, except unique weighting factor was assigned to all the grid points. To avoid inconsistency between quantum mechanical calculations and molecular modeling, the model peptide is further optimized at molecular mechanics level with main chain dihedral angles fixed before the calculation of the conformational energy on molecular mechanical level at each grid point, during which generalized Born model is employed. Difference in solvation models at quantum mechanics and molecular mechanics levels makes this parameterization procedure less straightforward. All force field parameters other than main chain torsions are taken from existing AMBER force field. With these new main chain torsion terms, we have studied small benchmark models and folded protein in aqueous solution. We show that the new force fields give an excellent agreement with experiments in J coupling, chemical shifts, and secondary structure populations. The results demonstrate that2D main chain torsion is effective in delineating the energy variation associated with rotations along main chain dihedrals.For the correlation of electrostatic term, our group develops polarized protein-specific charge (PPC). The explicitly polarized force field model is indispensable in the simulation of protein crystal due to its particular electrostatic environment which is different from that in water solution. A250ns molecular simulation employing the PPC was carried out to study the crystal of toxin protein II from the scorpion Androctonus australis Hectorhas, and the crystal stability is compared with that employing AMBER99SB force field. Results show that PPC outperforms AMBER99SB in maintaining the lattice structure. Under PPC, the monomer in subunit cell and the lattice in supercell are more stable with smaller RMSDs and the lattice atomic fluctuations are more in line with the crystallographic B-factors. Most of the interactions at each interface in X-ray structure are preserved under PPC. Nevertheless, the hydrogen bond between Asp53and Gln37and the cation-π interaction between Arg56and His64cannot be well maintained no matter whether PPC or AMBER99SB force field was utilized. Therefore, joint optimization of van der Waals interaction parameters to match with the new charge model is indispensable.