Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Thursday Speaker Abstracts

ALLOSTERIC COMMUNICATION AND KINETIC REGULATION IN MEMBRANE PROTEINS Hossein Batebi Department of Physics, Free University of Berlin, Berlin, Germany A major open question in GPCR biology is how a small chemical change, for example ligand protonation or the release and rebinding of nucleotides, can trigger structural adjustments that spread through the receptor–G protein complex and shape signaling outcomes. Although we now have many high-resolution structures, they do not explain how these long-range effects emerge.Even when intermediate states are characterized using exceptionally long MD simulations or time-resolved cryo-EM, such as in our recent works on β 2AR coupled to GDP bound and GTP-boundGs, applying conventional network analyses to these data reveals only correlated motions and still fails to identify the specific routes through which mechanical information flows. Moreover, since microsecond to millisecond MD simulations and time resolved cryo-EM are extremely costly, dynamic processes such as ligand binding, ligand dissociation, and nucleotide exchange are often modeled with enhanced sampling methods to generate free-energy profiles at lower computational cost. Yet, while PMFs map the energy landscape, they ignore spatially varying friction that exerts a major influence on the kinetics of conformational rearrangements. As a result, we still lack a quantitative framework that links chemistry at one site to the kinetics and specificity of signaling tens of ångströms away. To overcome these gaps, we developed two complementary methods that together provide a mechanistic description of allosteric communication and kinetics in membrane proteins. The first is a force-flow framework that tracks how efficiently mechanical signals propagate through the protein. By identifying the principal transmission modes and the residues that act as dominant relay points, this method isolates the minimal allosteric network responsible for long-range control. The second is a friction-aware kinetic model that uses enhanced sampling and solvent force autocorrelations to compute position-dependent friction and accurate mean first passage times along key reaction coordinates. This approach uncovers kinetic bottlenecks that are invisible in standard PMFs and directly links local chemical events to global signaling timescales. Our developed methods, when combined, fill the gap between structural links and kinetic processes, making the mechanisms that regulate GPCR activation and pathway preference quantitatively accessible.

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