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New Biological Frontiers Illuminated by Molecular Sensors and Actuators
Tuesday Speaker Abstracts
Theories Describing Sensors and Responders Reveal Important Allosteric Sites in Enzymes
Lee-Wei Yang
.
National Tsing Hua University, Hsinchu, Taiwan.
Accumulated experimental and theoretical evidences have shown that protein functions as a
physiochemically connected network. Allostery, understood in this new context, is a
manifestation of residue communicating over remote sites via this network and hence a recently
rising interest in identifying communication pathways mediating allosteric controls. In this study,
we demonstrate that a new formulation of linear response theory (LRT) can describe a two-stage
conformational relaxation- 1. ligand-induced conformational changes at a few tens to a hundred
of picoseconds and 2. an early molecular ‘twitch’ that is faster than conformational relaxation by
an order of magnitude. Predictions based on LRT agree with observations from site-specific UV
resonance Raman, time-resolved X-ray and sound speed in a condensed medium. With the
computational ease of the current implementation, we can easily perturb the protein network by
thousands of times where time-resolved atomic trajectories can be tracked following each
perturbation. Frequently used ‘communication centers’ are identified and it is found by
experiments that mutations of these centers, many remote from the catalytic site, would greatly
impact the hydride transfer rate in DHFR. Mutations on those that do not serve as
communication centers impact the catalysis minimally. We also show the signal propagation is
directional, highly anisotropic and need not be reciprocal. We favorably consider the method’s
applicable future in probing functionally sensitive distant mutants by the physical approach
herein proposed.