Deriving Effective Molecular Dynamics Potentials Using Iterative Boltzmann Inversion

Molecular dynamics (MD) is a powerful tool used to investigate protein folding and dynamics. The energy term in the Hamiltonian governing the dynamics of backbone dihedral angles has received a staggering amount of attention in recent years. Generally, with some exceptions, gas phase QM energy calculations are used to generate parameters of the dihedral energy functionals for a small group of amino acids, which are then shared among other amino acids. Recent work has demonstrated MD force fields which follow this template can not produce accurate amino acid residue-specific conformational dynamics in the unfolded state. We posit this can negatively affect computational studies of intrinsically disordered proteins (IDPs), which do not adopt a folded state and can be associated with diseases. Here, we attempt to modify the backbone dihedral parameters of glycine, the simplest amino acid, using a reference Ramachandran distribution derived from comprehensive set of spectroscopic data, which includes the effects of the aqueous environment, using the iterative Boltzmann inversion method. Improving the conformational dynamics of glycine will motivate a reparameterization of the dihedral terms for all amino acids using experimental data such that simulations can capture intrinsic conformational preferences of amino acid residues in water and potentially improve simulations of IDPs.