Monte Carlo and dynamics simulations of cdk5 Kinase inhibitor peptides p5 in aqueous solution

Tuesday, October 09, 2012 — Poster Session I
1:00 p.m. – 3:00 p.m	Natcher Conference Center, Building 45	NINDS	BIOINFO-3

Authors

• A. Cardone
• S. Hassan
• M. Brady
• R. Sriram
• H. Pant

Abstract

Protein function depends on shape changes triggered by protein interactions. Insights into protein interactions enable the understanding of pathologies caused by the deregulation of protein functions. The interaction between the kinase cdk5 and its activator p35 is fundamental in neuronal development and survival. Truncation of p35 results in the pathological activator p25 which deregulates cdk5. The resulting hyperphosphorylation of protein Tau is a pathogenic hallmark of neurodegenerative diseases. A study conducted at NINDS led to the identification of fragments of p35, which inhibit cdk5-p25 pathologic activity. Initially a 125-residue peptide called CIP was identified, too large for a successful therapeutic reagent. Then a smaller 24-residue peptide called p5 was derived from CIP. The structure of p5 is not known. Monte Carlo simulations of p5 were conducted to explore the conformational space and determine the structural families playing a role in kinase inhibition. Based on these calculations, molecular dynamics simulations were performed to refine the structures in solution and infer physico-chemical signatures that may play a role in inhibition. Electrostatics and hydrophobic interactions as well as specific hydrogen bonds appear to be the main contributions to binding. Experimental single-point mutations are proposed to decrease and increase cdk5-p5 affinity.

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