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

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Author(s): Antonio Cardone; Sergio Hassan; Mary C. Brady; Ram D. Sriram; Harish C. Pant;
Title: Monte Carlo and dynamics simulations of cdk5 Kinase inhibitor peptides p5 in aqueous solution
Published: July 20, 2012
Abstract: Protein function depends on shape changes that are triggered by interactions with other molecules. Insights into protein dynamics and interactions enable the understanding of certain pathologies, which may be caused by the deregulation of protein functions. The interaction between the cyclin- dependent kinase cdk5 and its activator p35 is fundamental in neuronal development and survival. Stress-induced truncation of p35 results in the pathological activator p25, which deregulates cdk5, thus leading to cdk5 hyperactivity. The resulting hyperphosphorylation of protein Tau and neurofilaments is a pathogenic hallmark of certain neurodegenerative diseases. A study conducted at the National Institute of Neurological Diseases and Strokes led to the identification of truncated fragments of p35, which have been shown to inhibit cdk5-p25 pathologic activity. Initially a 125- residue peptide called CIP was identified. Since CIP is too large for a successful therapeutic reagent, a smaller and more effective 24-residue peptide called p5 was derived from CIP. The structure of p5 in aqueous solution at physiological conditions is not known. Monte Carlo simulations of p5 were conducted to explore the conformational space of the peptide and determine the main structural families that may play a role in the 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 binding and inhibition. Electrostatics and hydrophobic interactions, as well as specific hydrogen bonds between charged amino acids appear to be the main contributions to binding. Experimental single-point mutations are proposed to decrease and increase cdk5-p5 affinity.
Keywords: Molecular dynamics; Monte Carlo simulations; neurodegenerative diseases
Research Areas: Information Delivery Systems, Drugs/Pharmaceuticals
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