Molecular dynamics simulations of conformational behavior of linear RGD peptidomimetics and cyclic prodrugs in aqueous and octane solutions

Journal of Biomolecular Structure & Dynamics
Janaki MahadevanKrysztof Kuczera

Abstract

Conformations available to a class of cyclic prodrugs and corresponding linear RGD peptidomimetics were explored using 1 ns length molecular dynamics simulations performed with the program CHARMM. Water and octane, modeled explicitly, were used as solvents to mimic the change of the environment experienced by the solutes upon partition from water to membrane in the trans-cellular transport process. In water, the linear peptidomimetics tended to populate extended-like structures, characterized by strong favorable interactions with solvent and low intrinsic stability. In these extended conformations the charged termini are able to assume large distances, above 15 A for the longest systems. These linear peptidomimetics have been found to exhibit the highest potency in experimental studies, in accord with the trends experimentally observed for RGD peptides. In contrast, in octane compact conformers of the linear peptidomimetics were favored, with all charged groups aggregated and shielded from solvent, exhibiting high intrinsic stability and weak solute-solvent interactions. Our calculations predict a large unfavorable energy change for transferring the linear systems from water to octane, in agreement with experimental findings th...Continue Reading

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Citations

Jun 7, 2008·Journal of Biomolecular Structure & Dynamics·Y HoundonougboG S Jas
Apr 21, 2006·Journal of Pharmaceutical Sciences·Tian-Xiang Xiang, Bradley D Anderson
Nov 1, 2005·Journal of Pharmaceutical Sciences·Stephanie L KrogmeierElizabeth M Topp
Nov 10, 2006·Advanced Drug Delivery Reviews·Tian-Xiang Xiang, Bradley D Anderson

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