Using PC clusters to evaluate the transferability of molecular mechanics force fields for proteins

Abstract

The transferability of molecular mechanics parameters derived for small model systems to larger biopolymers such as proteins can be difficult to assess. Even for small peptides, molecular dynamics simulations are typically too short to sample structures significantly different than initial conformations, making comparison to experimental data questionable. We employed a PC cluster to generate large numbers of native and non‐native conformations for peptides with experimentally measured structural data, one predominantly helical and the other forming a β‐hairpin. These atomic‐detail sets do not suffer from slow convergence, and can be used to rapidly evaluate important force field properties. In this case a suspected bias toward α‐helical conformations in the ff94 and ff99 force fields distributed with the AMBER package was verified. The sets provide critical feedback not only on force field transferability, but may also predict modifications for improvement. Such predictions were used to modify the ff99 parameter set, and the resulting force field was used to test stability and folding of model peptides. Structural behavior during molecular dynamics with the modified force field is found to be very similar to expectations, suggesting that these basis sets of conformations may themselves have significant transferability among force fields. We continue to improve and expand this data set and plan to make it publicly accessible. The calculations involved in this process are trivially parallel and can be performed using inexpensive personal computers with commodity components. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 21–31, 2003