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2016 ; 12
(1
): 274-80
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Analysis of Multidomain Protein Dynamics
#MMPMID26675644
Roy A
; Hua DP
; Post CB
J Chem Theory Comput
2016[Jan]; 12
(1
): 274-80
PMID26675644
show ga
Proteins with a modular architecture of multiple domains connected by linkers
often exhibit diversity in the relative positions of domains, while the domain
tertiary structure remains unchanged. The biological function of these modular
proteins, or the regulation of their activity, depends on the variation in domain
orientation and separation. Accordingly, careful characterization of interdomain
motion and correlated fluctuations of multidomain systems is relevant for
understanding the functional behavior of modular proteins. Molecular dynamics
(MD) simulations provides a powerful approach to study these motions in atomic
detail. Nevertheless, the common procedure for analyzing fluctuations from MD
simulations after rigid-body alignment fails for multidomain proteins; it greatly
overestimates correlated positional fluctuations in the presence of relative
domain motion. We show here that expressing the atomic motions of a multidomain
protein as a combination of displacement within the domain reference frame and
motion of the relative domains correctly separates the internal motions to allow
a useful description of correlated fluctuations. We illustrate the methodology of
separating the domain fluctuations and local fluctuations by application to the
tandem SH2 domains of human Syk protein kinase and by characterizing an effect of
phosphorylation on the dynamics. Correlated motions are assessed from a distance
covariance rather than the more common vector-coordinate covariance. The approach
makes it possible to calculate the proper correlations in fluctuations internal
to a domain as well as between domains.
|*Molecular Dynamics Simulation
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/chemistry/metabolism
[MESH]
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