Seminars of the Focus Area Complex Systems

Prof. Dr. C. Beta, Prof. Dr. K. Dethloff, Prof. Dr. R. Engbert, Prof. Dr. M. Holschneider, Prof. Dr. W. Huisinga, Prof. Dr. Ralf Metzler, Prof. Dr. A. Pikovsky, Prof. Dr. S. Reich, Prof. Dr. M. Rosenblum, Prof. Dr. G. Rüdiger, Prof. Dr. T. Scheffer, Prof. Dr. F. Scherbaum, Prof. Dr. J. Selbig, Prof. Dr. F. Spahn


Speaker: Joachim Dzubiella, Helmholtz Zentrum Berlin

Title: Solvent fluctuations in hydrophobic cavity-ligand binding kinetics * Colloquium on Complex and Biological Systems

Time: Fri, Apr 26, 2013, 10:15am

Place: bldg 28, room 0.108

Water plays a crucial part in virtually all protein–ligand binding processes in and out of equilibrium. Here, we investigate the role of water in the binding kinetics of a ligand to a prototypical hydrophobic pocket by explicit-water molecular dynamics (MD) simulations and implicit diffusional approaches. The concave pocket in the unbound state exhibits wet/dry hydration oscillations whose magnitude and time scale are significantly amplified by the approaching ligand. In turn, the ligand’s stochastic motion intimately couples to the slow hydration fluctuations, leading to a sixfold-enhanced friction in the vicinity of the pocket entrance. The increased friction considerably decelerates association in the otherwise barrierless system, indicating the importance of molecular-scale hydrodynamic effects in cavity–ligand binding arising due to capillary fluctuations. We derive and analyze the diffusivity profile and show that the mean first passage time distribution from the MD simulation can be accurately reproduced by a standard Brownian dynamics simulation if the appropriate position-dependent friction profile is included. However, long-time decays in the water–ligand (random) force autocorrelation demonstrate violation of the Markovian assumption, challenging standard diffusive approaches for rate prediction. Remarkably, the static friction profile derived from the force correlations strongly resembles the profile derived on the Markovian assumption apart from a simple shift in space, which can be rationalized by a time–space retardation in the ligand’s downhill dynamics toward the pocket. The observed spatiotemporal hydrodynamic coupling may be of biological importance providing the time needed for conformational receptor–ligand adjustments, typical of the induced-fit paradigm.

REF: P. Setny, R. Baron, P. Kekenes-Huskey, J. A. McCammon, and J. Dzubiella, Proc. Natl. Acad. Sci USA (PNAS) 110, 1197-1202 (2013).

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Students' seminar: Theoretical Physics, PIK, Modeling & TSA Berlin-Potsdam-Colloquia: PhysGesellschaft Berlin, TU Berlin, Pro Physik, AIP, AEI, MPI-KGF, GFZ, HMI, PIK, AWI, Max Planck Institute for the History of Science, Mathematik, DPG Disputationen, & Vorschau UP

Udo Schwarz, Zentrum für Dynamik komplexer Systeme,
Universität Potsdam, Campus Golm Karl-Liebknecht-Str. 24, 14476 Potsdam, building 28, room 2.107
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DFG SFB 1294

DFG Sonderforschungsbereich 1294 Data assimilation

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DFG Schwerpunktprogramm 1488 Planetmag

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