Dynamics of an adenine-adenine RNA conformational switch from discrete path sampling

Abstract

The study of 'rare event' dynamics can be challenging despite continuing advances in computer hardware. A wide variety of methods based on the master equation approach have been developed to tackle such problems, where the focus is on Markovian dynamics between appropriately defined states. In this contribution we employ the discrete path sampling approach to characterize pathways and rates for an adenineadenine RNA conformational switch. The underlying free energy landscape supports competing structures separated by relatively high barriers, with the two principal funnels leading to the major and minor conformations identified by NMR experiments. The interconversion time scale is predicted to be a few hundred seconds, consistent with the experimental lower bound estimates. We find that conformational switching occurs via stacked intermediates, through a sliding mechanism, in agreement with a previous simulation study. By retaining full dimensionality, and avoiding lowdimensional projections, the mechanism can be described at an atomistic level of detail.

A multifunnel energy landscape encodes the competing α-helix and β-hairpin conformations for a designed peptide

“…The coexistence of these folds results in a low-temperature peak in the heat capacity profile, which is reminiscent of solid-solid type transitions observed in atomic and molecular clusters, 91 as well as biomolecular switches. [97][98][99] Mutation of Tyrosine at position 12 to a Serine alters the landscape topography significantly, and lifts the degeneracy in agreement with the experiment of Araki and Tamura. 40 .…”

Energy Landscapes for Base-Flipping in a Model DNA Duplex

“…The potential energy landscape (PEL) framework used in the present work does not employ reaction coordinates. In recent studies, − we have successfully exploited the PEL framework to probe complex conformational transitions in nucleic acids, and rationalize key experimental findings. We note that the order parameters used for analysis during this investigation were only used in postprocessing to identify DNA duplex structures with a particular base present in an extrahelical state.…”

Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides

“…Discrete path sampling (DPS) , was employed for further exploration of the PEL. The DPS procedure has been previously used to construct databases of stationary points (kinetic transition network) for a wide range of systems − and provide insight into conformational transitions spanning a hierarchy of time scales. Within the DPS framework, the connectivity between different regions of the PES is described in terms of discrete paths, consisting of an interconnected sequence of local minima and intervening transition states.…”