Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

48-POS Board 8 Competition and Cooperation of Electrostatic-Steering and Conformational Dynamics in the Binding of Calcineurin's Intrinsically-disordered Recognition Domain with Calmodulin

Bin Sun 2 , Erik C. Cook 2 , Trevor P. Creamer 2 , Peter M. Kekenes-Huskey 2 . 1 n/a, Lexington, USA, 2 University of Kentucky, Lexington, KY, USA.

Calcineurin (CaN) is a serine/threonine phosphatase that regulates a variety of physiological and pathophysiological processes in most mammalian tissue. It has been established that the calcineurin (CaN) regulatory domain is highly disordered when inhibiting CaN, yet it undergoes a disorder-to-order transition upon binding calmodulin (CaM) to activate the phosphatase. The prevalence of polar and charged amino acids in the RD domain implicate electrostatic interactions in mediating CaM binding, yet it unclear whether properties of the RD conformational ensemble, such as its effective volume and accessibility of its CaM binding motif help or hinder its ability to participate in protein-protein recognition events. In the present study, we investigated via computational modeling the extent to which electrostatics and structural disorder co-facilitate or hinder CaM/CaN association kinetics. We examined several peptides containing the CaM binding motif, for which lengths and amino acid charge distributions were varied, to isolate the contributions of electrostatics versus conformational diversity to predicted, diffusion-limited association rates via microsecond-scale molecular dynamics (MD) and Brownian dynamics (BD) simulations. Our results indicate that the RD amino acid composition and sequence length influence both the dynamic availability of conformations amenable to CaM binding, as well as long-range electrostatic interactions to steer association. These findings provide intriguing insight into the interplay between conformational diversity and electrostatically-driven protein-protein association involving CaN, which are likely to extend to wide-ranging processes regulated by intrinsically-disordered proteins.

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