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 beta-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 alpha-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.

Comparison of multiple Amber force fields and development of improved protein backbone parameters

“…Similar to work that we previously published 12 for ff94 and ff99, we used "decoy analysis" to test the capability of the force field to identify the experimentally determined native structure as that with the lowest potential energy. Three systems were used for decoy analysis: trpzip2 42 (SWTWENGKWTWK-NH 2 ), Baldwin type 43 alanine based α-helical peptide 44 (Ace-GGG(KAAAA) 3 K-NH 2 ) and trpcage miniprotein 45 (NLYIQWLKDGGPSSGRPPPS).…”

“…Three systems were used for decoy analysis: trpzip2 42 (SWTWENGKWTWK-NH 2 ), Baldwin type 43 alanine based α-helical peptide 44 (Ace-GGG(KAAAA) 3 K-NH 2 ) and trpcage miniprotein 45 (NLYIQWLKDGGPSSGRPPPS). The decoys for the three systems were generated by a number of unrestrained as well as forced MD simulations at 300K as described previously 12 .…”

“…Even though both ff99 and, particularly, ff94 parameter sets have been successfully used for many years, improvement in conformational sampling due to increased computer power and algorithmic advances revealed that both force fields over-stabilize α-helical peptide conformations 12,13 . On the other hand, the changes introduced in the less frequently used ff96 were observed to overestimate β-strand propensity [14][15][16][17] .…”

“…Because the backbone dihedral parameters are shared by all amino acids, regardless of the type of sidechain, their cumulative effect is most likely responsible for the bias towards the specific secondary structure. This recently motivated us 12,18 and others 13,19 to revisit backbone dihedral parametrization for ff94/ff99. Garcia and Sanbonmatsu 13 simply zeroed the torsion potential for φ and ψ (although as we explain below, only some of the φ/ψ terms were removed) and noted improved agreement with experimental helix-coil parameters.…”

“…This definition of dihedrals was originally implemented in ff94, with φ and ψ fit independently to glycine data and φ′ and ψ′ used to adjust the behavior for alanine. Later modifications of ff94, such as ff96, ff99, Garcia's 13 , Pande's 19 and ours 12,18 only changed the first set of φ/ψ terms, using them to adjust backbone preferences for alanine. Thus the new ϕ and ψ parameters were fit in the presence of the ff94 alanine-based φ′ and ψ′, and will only give their intended behavior when they accompany these φ′ and ψ′ dihedrals.…”