Molecular Simulation of Conformational Pre-Organization in Cyclic RGD Peptides

Journal of Chemical Information and Modeling
Amanda E WakefieldVincent A Voelz

Abstract

To test the ability of molecular simulations to accurately predict the solution-state conformational properties of peptidomimetics, we examined a test set of 18 cyclic RGD peptides selected from the literature, including the anticancer drug candidate cilengitide, whose favorable binding affinity to integrin has been ascribed to its pre-organization in solution. For each design, we performed all-atom replica-exchange molecular dynamics simulations over several microseconds and compared the results to extensive published NMR data. We find excellent agreement with experimental NOE distance restraints, suggesting that molecular simulation can be a useful tool for the computational design of pre-organized solution-state structure. Moreover, our analysis of conformational populations estimates that, despite the potential for increased flexibility due to backbone amide isomerizaton, N-methylation provides about 0.5 kcal/mol of reduced conformational entropy to cyclic RGD peptides. The combination of pre-organization and binding-site compatibility explains the strong binding affinity of cilengitide to integrin.

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Citations

Apr 1, 2016·Journal of Chemical Theory and Computation·Sean M McHughYu-Shan Lin
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Jan 12, 2021·Chemical Reviews·Jovan DamjanovicYu-Shan Lin
Apr 28, 2021·Journal of Chemical Information and Modeling·Yunhui GeVincent A Voelz
May 29, 2021·Frontiers in Molecular Biosciences·Vincent A VoelzRobert M Raddi
Jun 15, 2021·Journal of Chemical Information and Modeling·Matthew F D HurleyVincent A Voelz
Mar 29, 2018·The Journal of Physical Chemistry. B·Diana P SloughYu-Shan Lin
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Dec 23, 2021·Physical Chemistry Chemical Physics : PCCP·Anna S KamenikSereina Riniker

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