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We present the Rate from Event Durations (RED) scheme, a new scheme that more efficiently calculates rate constants using the weighted ensemble path sampling strategy. This scheme enables rate-constant estimation from shorter trajectories by incorporating the probability distribution of event durations, or barrier-crossing times, from a simulation. We have applied the RED scheme to weighted ensemble simulations of a variety of rare-event processes that range in complexity: residue-level simulations of protein conformational switching, atomistic simulations of Na+/Cl− association in explicit solvent, and atomistic simulations of protein–protein association in explicit solvent. Rate constants were estimated with up to 50% greater efficiency than the original weighted ensemble scheme. Importantly, our scheme accounts for the systematic error that results from statistical bias toward the observation of events with short durations and reweights the event duration distribution accordingly. The RED scheme is relevant to any simulation strategy that involves unbiased trajectories of similar length to the most probable event duration, including weighted ensemble, milestoning, and standard simulations as well as the construction of Markov state models. [ABSTRACT FROM AUTHOR]

We present a new force field, AMBER ff15ipq-m, for simulations of protein mimetics in applications from therapeutics to biomaterials. This force field is an expansion of the AMBER ff15ipq force field that was developed for canonical proteins and enables the modeling of four classes of artificial backbone units that are commonly used alongside natural α residues in blended or "heterogeneous" backbones: chirality-reversed D-α-residues, the Cα-methylated α-residue Aib, homologated β-residues (β3) bearing proteinogenic side chains, and two cyclic β residues (βcyc; APC and ACPC). The ff15ipq-m force field includes 472 unique atomic charges and 148 unique torsion terms. Consistent with the AMBER IPolQ lineage of force fields, the charges were derived using the Implicitly Polarized Charge (IPolQ) scheme in the presence of explicit solvent. To our knowledge, no general force field reported to date models the combination of artificial building blocks examined here. In addition, we have derived Karplus coefficients for the calculation of backbone amide J-coupling constants for β3Ala and ACPC β residues. The AMBER ff15ipq-m force field reproduces experimentally observed J-coupling constants in simple tetrapeptides and maintains the expected conformational propensities in reported structures of proteins/peptides containing the artificial building blocks of interest—all on the μs timescale. These encouraging results demonstrate the power and robustness of the IPolQ lineage of force fields in modeling the structure and dynamics of natural proteins as well as mimetics with protein-inspired artificial backbones in atomic detail. [ABSTRACT FROM AUTHOR]

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-Qsolv derives bonded parameters in the context of the ff15ipq solution phase charge set. Second, ff15ipq-Vac 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-Qsolv increases stability in a number of α-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 AAQAA3 by 50% or more, forming long-lived α-helices in simulations of a β-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-Qsolv 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-Vac 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-Qsolv 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. [ABSTRACT FROM AUTHOR]