Theory and simulation of diffusion-influenced, stochastically gated ligand binding to buried sites.
We consider the diffusion-influenced rate coefficient of ligand binding to a site located in a deep pocket on a protein; the binding pocket is flexible and can reorganize in response to ligand entrance. We extend to this flexible protein-ligand system a formalism developed previously [A. M. Berezhkovskii, A, Szabo, and H.-X. Zhou, J. Chem. Phys. 135, 075103 (2011)] for breaking the ligand-binding problem into an exterior problem and an interior problem. Conformational fluctuations of a bottleneck or a lid and the binding site are modeled as stochastic gating. We present analytical and Brownian dynamics simulation results for the case of a cylindrical pocket containing a binding site at the bottom. Induced switch, whereby the conformation of the protein adapts to the incoming ligand, leads to considerable rate enhancement.
Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, USA.
Jorge L
JL
Barreda
Huan-Xiang
HX
Zhou
D001665:Binding Sites; D003198:Computer Simulation; D004058:Diffusion; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013269:Stochastic Processes
D008024:Ligands; D011506:Proteins