Real Time Exploration of Allosteric Communication: Experiment, MD, and Low-Dimensional Modelling

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Abstract

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Allostery represents a fundamental mechanism for protein signaling and regulation. While little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on photoswitchable proteins by Hamm and coworkers have indicated that the allosteric transition occurs on a wide range of timescales (up to ten decades), which suggests a multi-step process on a hierarchical energy landscape. Performing extensive nonequilibrium molecular dynamics (MD) simulations for various PDZ domains, the modeling of the experiments reproduces the measured timescales in excellent agreement. To elucidate the underlying mechanism, we consider the time evolution of interresidue contact distances. Using MoSAIC correlation analysis, we identify clusters of highly correlated contacts in various regions of the proteins, which mediate long-range couplings via rigid secondary structure elements. This suggests a model of weakly interacting contact clusters, which reveals that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and may occur in a non-local fashion. Moreover, the model explains the multiple timescales (from pico- to microseconds) observed in experiment by individual structural subprocess which are coupled in a hierarchical manner.

 

[1] G. Stock and Peter Hamm, A Nonequilibrium Approach to Allosteric Communication, Phil. Trans. B 373, 20170187 (2018).

[2] G. Diez, D. Nagel and G. Stock, Correlation-based feature selection to identify functional dynamics in proteins, J. Chem. Theory Comput. 18, 5079 (2022).

[3] A. Ali, E. Dorbath and G. Stock, Allosteric communication mediated by protein contact clusters: A dynamical model,  J. Chem. Theory Comput. 20, 10731 (2024),

 

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About the Speaker

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Prof. Dr. Gerhard Stock is a distinguished W3 Professor at the University of Freiburg's Institute of Physics in Germany, with an impressive academic career spanning decades. He earned his Diploma in Physics in 1987 and his Doctorate in Chemistry in 1990, both from the Technical University of Munich. His career includes significant roles such as C4 Professor at the University of Frankfurt (2000-2009) and Heisenberg Professor at the University of Freiburg (1997-2000), alongside a habilitation in Theoretical Chemistry in 1996. Stock was a postdoctoral fellowship at the University of California, Berkeley. Renowned for his contributions to theoretical chemistry and physics, his research focuses on protein dynamics, quantum energy flow, and nonadiabatic processes, with over 10 seminal publications in top journals like PNAS and Physical Review Letters, showcasing his expertise in molecular simulations and allosteric transitions.