149
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.
