Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

96-POS Board 49 Ligand Gating, Cavity Fluidity and Conformational Selection Observed for T4 Lysozyme Cavity Mutants Sampled by aMD Simulation. Victoria Feher 1 , Levi Pierce 3 , J. Andrew McCammon 2 , Rommie Amaro 1 . 1 University of California at San Diego, La Jolla, USA, 2 Howard Hughes Medical Institute, La Jolla, CA, USA, 3 Schrodinger, Inc., New York, CA, USA. Native protein cavities, packing defects and hydrophobic core plasticity are thought to play an important role in protein stability, generation of conformational substates, function and allostery. Presently, we explore the conformational landscape of wild type and engineered N-terminal lobe cavities of T4 lysozyme as a model system with recently advanced long time-scale accelerated molecular dynamic simulation on GPU processors. Four systems were considered, each sampled for 1.2 – 1.6 microseconds; wild type, apo and benzene bound L99A mutant, and a triple mutant L99A/G113A/R119P representing a high energy L99A conformation that does not bind benzene. To facilitate conformational sub-state analysis, simulations were clustered on the basis of N- terminal lobe cavity volumes rather than RMSD. Analysis and comparison of the conformational sub-states sampled by these different systems demonstrates cavity size impact on the number of conformational sub-states available to the protein, while maintaining native-like secondary structure. While it is not surprising that the apo form L99A mutant has the largest distribution of conformational sub-states, the distribution of cavity shapes is dramatic and will be compared with extensive published NMR dynamics studies. Rare event concerted side-chain rearrangement combined with secondary structure opening reveal several regions with gated-motions available for solvent exchange to the hydrophobic interior of the cavity mutant, however only one presents a large enough path for known hydrophobic ligands to exchange. Finally, cavity size appears to impact the frequency the inter- lobe hinge bending motion but not the magnitude.

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