Molecular modeling of interaction between sAnk157-122 and obscurin6322-6339 in striated muscle

COMP 248

Taiji Oashi, toashi@rx.umaryland.edu1, Ben Busby, bbusb001@umaryland.edu2, Chris D. Willis, cwill015@umaryland.edu2, Robert J. Bloch, rbloch@umaryland.edu2, and Alexander D. MacKerell Jr., amackere@rx.umaryland.edu1. (1) Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, (2) Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201
Binding of obscurin (obsc) to the muscle-specific small ankyrin1 (sAnk1) is important for organizing the sarcoplasmic reticulum in striated muscle. Experimental work investigating this interaction has been performed on obsc6322-6339 and sAnk157-122. We used molecular modeling methods to obtain additional information on this interaction. Initial interaction between obsc6322-6339 and sAnk157-122 was modelled using 10,000 Brownian dynamics simulations followed by the minimization of the complex, with solvation treated using the Generalized-Born method. Obsc is predicted to interact with R67,R68,R69,K73,K100,K101,R104,K105,R108 in sAnk1, in agreement with experimental results. 30ns MD simulations were then performed on six selected obsc-sAnk1 complexes. Results show that the alpha helical conformation of obsc is maintained in the complex, where it is stabilized by the interaction with the positively charged binding groove in sAnk1. Results from the simulations also predicted that K6337 on obsc interacts with D111 on sAnk1, a prediction that we recently confirmed by experiments. The modeling observed the dynamic and heterogeneic properties in sAnk157-122-obsc6322-6339 interaction.

Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster

Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009