Comparative Study of Molecular Mechanics Force Fields for -Peptidic Foldamers: Folding and Self-Association

Computer-assisted study and design of non-natural peptidomimeticsis increasingly important in the development of novel constructs withwidespread applicability. Among these methods, molecular dynamicscan accurately describe monomeric as well as oligomeric states ofthese compounds. We studied seven different sequences composed ofcyclic and acyclic & beta;-amino acids, the closest homologues ofnatural peptides, and compared the performance on them of three forcefield families in which specific modifications were made to improvereproduction of & beta;-peptide structures. Altogether 17 systemswere simulated, each for 500 ns, testing multiple starting conformationsand in three cases also oligomer formation and stability from eight & beta;-peptide monomers. The results indicated that our recentlydeveloped CHARMM force field extension, based on torsional energypath matching of the & beta;-peptide backbone against quantum-chemicalcalculations, performs best overall, reproducing the experimentalstructures accurately in all monomeric simulations and correctly describingall the oligomeric examples. The Amber and GROMOS force fields couldonly treat some of the seven peptides (four in each case) withoutfurther parametrization. Amber was able to reproduce the experimentalsecondary structure of those & beta;-peptides which contained cyclic & beta;-amino acids, while the GROMOS force field had the lowest performancein this sense. From the latter two, Amber was able to hold togetheralready formed associates in the prepared state but was not able toyield spontaneous oligomer formation in the simulations.