In order to computationally design peptidomimetics that are pre-organized in solution, accurate molecular simulation methods are needed. To test the ability of simulations to accurately predict conformational flexibility, we are studying the solution-state conformational properties of 28 cyclic Arg-Gly-Asp (RGD) peptides that are variants of the anti-cancer drug Cilengitide, a highly selective and potent inhibitor of av�3 integrin.  Much of the binding affinity of Cilengitide can be ascribed to its pre-organization in solution, which thermodynamically favors binding. There is extensive NMR data available for these Cilengitide variants including NOE data, against which we can compare our simulation results.  We used all-atom replica-exchange molecular dynamics (REMD) simulations to predict conformational populations of the RGD peptides in solution. The accuracy of these results suggests that such methods can be useful for computational design.

Conformational properties of cyclic RGD peptides by molecular simulation

248th National Meeting (2014)

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