The evaluation of protein-ligand binding free energies using advanced potential energy function

Abstract

Electronic polarisation is one of the components that plays an important role in many biomolecular systems. The effects of polarisation will act differently depending on the local environment of the system, such as in DNA, proteins and membranes. Traditionally, molecular mechanical force fields describe electrostatics as the interactions of fixed, atom-centred, point charges. Hence the past decade has seen many additions and improvements to existing force fields to better correlate dynamics with experimental observations. A better description of electrostatics by the inclusion of electronic polarisation is one such improvement. The AMOEBA polarisable force field is one of many possible models that is designed to be capable of capturing this effect. AMOEBA includes mutually polarising induced atomic dipoles at every atomic site, as well as a multipolar representation of fixed electrostatics.

To investigate applications of AMOEBA and where its successes over existing fixed-charge methods may lie, we first evaluate features and performance of the AMOEBA polarisable force field in simple systems based on the evaluation of solvation free energies for small molecules in a range of common organic solvents. Here, we pointed out several challenges and limitations of AMOEBA in this study involving non-aqueous solvents. Then, we further our investigation on more complex systems including protein-ligand interactions. Initially, clear cases of failure in fixed-point-charge force fields were identified by exploring the sensitivity of the calculated free energies to parameter sets and simulation protocols of protein-ligand systems, focusing on binding free energy calculations of the cytochrome c peroxidase protein using the AMBER force field. Finally, we use these results to inform binding free energy calculations for testing of the AMOEBA force field. We discuss the implications of these results for better understanding and improving AMOEBA to aid its full implementation in other biological applications

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Identifiers

ORCID for Jonathan W. Essex: orcid.org/0000-0003-2639-2746

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