The folding of proteins and nucleic acids are challenging processes to study experimentally but are well suited to theoretical investigation via computer simulations. The treatment of nonbonded forces, particularly electrostatics, in molecular dynamics force fields is of paramount importance in simulating folding pathways the underlie biomolecular function, dysfunction, and disease. Protein conformational ensembles are influenced strongly by cooperativity in hydrogen bonding and competition for these interactions with water. Nucleic acids are stabilized by polar hydrogen bonding, nonpolar base stacking, and interactions among the strongly polarizing polyanionic phosphodiester backbone and ions. Given the importance of electrostatic interactions, we are applying a polarizable force field based on the classical Drude oscillator model in our simulations of amyloidogenic proteins and short RNA to determine the impact of electronic polarization on the folding pathways of these biomolecules. We have developed force field parameters for protein post-translational modifications (acetylation and phosphorylation) by targeting dipole moments, molecular polarizabilities, water interactions, and conformational potential energy scans of side chain torsions. Electronic polarization strongly impacts the potential energy surfaces, an observation that extends to nucleic acids. Nucleobase dipole moments are sensitive to their conformations along folding pathways and in noncanonical folds such as G-quadruplexes. We show that base dipole moments vary as a function of solvation and ion interactions that stabilize their native folds. In simulations of RNA r(gcUUCGgc) tetraloop, the sequence adopted a native-like fold in 4 µs and we monitored base dipole moments over time. As these bases adopt native hydrogen bonding geometries, their dipole moments shifted towards values observed in simulations of the folded structure. These new force field parameters and results of polarizable simulations amyloidogenic proteins, DNA GQs, and RNA tetraloops suggest that the Drude force field yields unique insights into electronic structure towards drug design and understanding biomolecular folding and interactions.

Nucleic acid and amyloidogenic protein folding and dynamics using a polarizable force field based on the classical drude oscillator model

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.