(582cz) Multiscale Investigation of Biomolecular Systems Dynamics

Global transitions of proteins, which usually occur on the time scale of microseconds or more, are beyond the capacity of full-atomic conventional molecular dynamics (MD) simulations. Due to this limitations elastic network models, such as the Anisotropic Network Model (ANM), have been widely used to simulate such transitions. However, a direct comparison between the global dynamics obtained by MD simulation long enough to potentially provide hints about global changes is still missing. Here we perform such comparison by analyzing the MD simulations of two systems, one longer than a millisecond on the equilibrium dynamics of bovine pancreatic trypsin inhibitor (BPTI) and the other, of several microseconds on the gating mechanism of an archaeal aspartate transporter, GltPh, that serves as a model for human excitatory amino acid transporters.¹ It is shown that, despite depending only on the contact topology, the ANM successfully captures the global dynamics of these extensive MD simulations and defines the pathways that underlie the passage between substates. In order to take advantage of such features while simulating at all-atom level, we  propose a new methodology² which deforms the structure collectively along the modes predicted by the ANM, while evaluating the interactions and energetics via a full-atomic MD simulations.  Application to adenylate kinase, an allosteric enzyme composed of three domains, CORE, LID and NMP, shows that an energy-barrier crossing occurs during the NMP movements and originates from a switch between interdomain salt bridges. In addition, we explore the functional transition mechanisms of the dopamine transporter (DAT), an integral membrane protein that terminates chemical neurotransmission in the central nervous system by removing dopamine from the synapse. An intermediate substate of DAT occluded to both the extra- and intracellular regions is identified along the transition between the inward- and outward-facing substates.

   1.   Gur M, Zomot E, Bahar I. Global Motions Exhibited by Proteins in Micro- to Milliseconds Simulations Concur with Anisotropic Network Model Predictions. Journal of Chemical Physics, 2013, submitted.

   2.   Gur M, Madura J, Bahar I. Global Transitions of Proteins Explored by a Multiscale Hybrid Methodology: Application to Adenylate Kinase. Biophysical Journal, 2013, submitted.