The general view of binding mechanisms has evolved from the early lock-and-key hypothesis to the more dynamic view of an ‘induced fit’ model to describe observed pharmacology. Although numerous examples of induced fit are known, there are currently no robust methods for prospectively exploring and predicting this complex dynamic behavior. A specific example is the steroid receptors the glucocorticoid and mineralocorticoid receptors. High-resolution X-ray structures revealed a large ligand induced loop movement. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all atom unbiased ligand exit and entrance simulations, implemented into the Protein Energy Landscape Exploration (PELE) method (1), corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role (2). Kinetic measurements reveal that the receptor residence time correlate with structural rearrangements observed in both structures and simulations. Analysis of the ligand binding energy landscape enabled us to accurately calculate the relative binding free energies of the studied ligands (2). References 1. R. Takahashi, V. A. Gil, V. Guallar ”Monte Carlo Free Ligand Diffusion with Markov State Model Analysis and Absolute Binding Free Energy Calculations.” Journal of Chemical Theory and Computation 10, 282-288, doi:10.1021/ct400678g (2014) 2. K. Edman, A. Hosseini, M. K. Bjursell, A. Aagaard, L. Wissler, A. Gunnarsson, T. Kaminski, C. Köhler, S. Bäckström, T. J. Jensen, A. Cavallin, U. Karlsson, E. Nilsson, D. Lecina, R. Takahashi, C. Grebner, S. Geschwindner, M. Lepistö, A. Hogner, V. Guallar “Ligand binding mechanism in steroid receptors; from conserved plasticity to differential evolutionary constraints.” Structure, accepted (2015).

Novel in silico approach for modeling the dynamic nature of proteins

251st National Meeting (2016)

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