Molecular Simulation of Conformational Pre-Organization in Cyclic RGD Peptides.
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.
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
Amanda E
AE
Wakefield
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
William M
WM
Wuest
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
Vincent A
VA
Voelz
D015195:Drug Design; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000737:chemistry*; D057786:Peptidomimetics / Q000737:chemistry; D011487:Protein Conformation; D013997:Time Factors
D010456:Peptides, Cyclic; D057786:Peptidomimetics; C507169:cyclic arginine-glycine-aspartic acid peptide