Links between the charge model and bonded parameter force constants in biomolecular force fields

Abstract

<p class="first" id="d4341779e182">The ff15ipq protein force field is a fixed charge model built by automated tools based on the two charge sets of the implicitly polarized charge method: one set (appropriate for vacuum) for deriving bonded parameters and the other (appropriate for aqueous solution) for running simulations. The duality is intended to treat water-induced electronic polarization with an understanding that fitting data for bonded parameters will come from quantum mechanical calculations in the gas phase. In this study, we compare ff15ipq to two alternatives produced with the same fitting software and a further expanded data set but following more conventional methods for tailoring bonded parameters (harmonic angle terms and torsion potentials) to the charge model. First, ff15ipq- <tt>Qsolv</tt> derives bonded parameters in the context of the ff15ipq solution phase charge set. Second, ff15ipq- <tt>Vac</tt> takes ff15ipq’s bonded parameters and runs simulations with the vacuum phase charge set used to derive those parameters. The IPolQ charge model and associated protocol for deriving bonded parameters are shown to be an incremental improvement over protocols that do not account for the material phases of each source of their fitting data. Both force fields incorporating the polarized charge set depict stable globular proteins and have varying degrees of success modeling the metastability of short (5–19 residues) peptides. In this particular case, ff15ipq- <tt>Qsolv</tt> increases stability in a number of <span class="inline-formula"> <math id="M1" overflow="scroll"> <mi>α</mi> </math> </span>-helices, correctly obtaining 70% helical character in the K19 system at 275 K and showing appropriately diminishing content up to 325 K, but overestimating the helical fraction of AAQAA ₃ by 50% or more, forming long-lived <span class="inline-formula"> <math id="M2" overflow="scroll"> <mi>α</mi> </math> </span>-helices in simulations of a <span class="inline-formula"> <math id="M3" overflow="scroll"> <mi>β</mi> </math> </span>-hairpin, and increasing the likelihood that the disordered p53 N-terminal peptide will also form a helix. This may indicate a systematic bias imparted by the ff15ipq- <tt>Qsolv</tt> parameter development strategy, which has the hallmarks of strategies used to develop other popular force fields, and may explain some of the need for manual corrections in this force fields’ evolution. In contrast, ff15ipq- <tt>Vac</tt> incorrectly depicts globular protein unfolding in numerous systems tested, including Trp cage, villin, lysozyme, and GB3, and does not perform any better than ff15ipq or ff15ipq- <tt>Qsolv</tt> in tests on short peptides. We analyze the free energy surfaces of individual amino acid dipeptides and the electrostatic potential energy surfaces of each charge model to explain the differences. </p>