Past Event: Oden Institute Seminar

Molecular Dynamics Simulations of Polynucleotide and its Partners

Serdal Kirmizialtin, ICES

Abstract

Molecular dynamics simulation (MD) serves as a valuable tool to understand biophysical processes. I will present two systems that we study using simulations and the new insight we have obtained. My first example will be modeling of ion-RNA interactions. Traditionally viewed as genetic messengers, RNA molecules have been recently discovered with diverse functions related to gene regulation and expression. Metal ions are an integral part of RNA structure and function; a few methods exist for quantitative characterization of the ion atmosphere and its influence on structure. Here, I present an experimental/theoretical collaboration that combines multiple-energy Anomalous Small-Angle X-ray Scattering and all-atom molecular dynamics simulations. The approach that combines experiment and simulation allows for more extensive investigations of ion-RNA interactions than provided by either method alone. We further compared our results with Poisson Boltzmann (PB) methods. We find excellent agreement in the number of excess ions around RNA between experiment, PB and MD, but the distribution of ions around RNA was different for magnesium ion in MD and PB. The second part of the talk will focus on one of the most important processes of life: How is the genetic code copied with such accurate precision? This process is controlled by a family of enzymes called DNA polymerase. We consider a specific member of this family, HIV reverse transcriptase (HIV RT). I will present new experimental and theoretical analysis of the role of structural transitions in HIV RT to select a correct substrate over a mismatch. We have found that a large conformational change occurring on the millisecond timescale locks the correct nucleotide at the active site, but promotes release of a mismatched nucleotide. Using the Milestoning method we were able to predict the long time scale conformational changes without giving up atomic detail description. The rates of transitions predicted by simulations are confirmed by Stopped-flow experiments. Our finding suggests that correct nucleotide is selected in the step of conformational change rather than the chemical step.