Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
83
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.