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The increasing availability of high-quality experimental data and first-principles calculations creates opportunities for developing more accurate empirical force fields for simulation of proteins. We developed the AMBER-FB15 protein force field by building a high-quality quantum chemical data set consisting of comprehensive potential energy scans and employing the ForceBalance software package for parameter optimization. The optimized potential surface allows for more significant thermodynamic fluctuations away from local minima. In validation studies where simulation results are compared to experimental measurements, AMBER-FB15 in combination with the updated TIP3P-FB water model predicts equilibrium properties with equivalent accuracy, and temperature dependent properties with significantly improved accuracy, in comparison with published models. We also discuss the effect of changing the protein force field and water model on the simulation results.

We present a united-atom model (gb-fb15) for the molecular dynamics simulation of hydrated liquid-crystalline dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayers. This model was constructed through the parameter-space minimization of a regularized least-squares objective function via the ForceBalance method. The objective function was computed using a training set of experimental bilayer area per lipid and deuterium order parameter. This model was validated by comparison to experimental volume per lipid, X-ray scattering form factor, thermal area expansivity, area compressibility modulus, and lipid lateral diffusion coefficient. These comparisons demonstrate that gb-fb15 is robust to temperature variation and an improvement over the original model for both the training and validation properties.

Beta-hairpins are substructures found in proteins that can lend insight into more complex systems. Furthermore, the folding of beta-hairpins is a valuable test case for benchmarking experimental and theoretical methods. Here, we simulate the folding of CLN025, a miniprotein with a betahairpin structure, at its experimental melting temperature using a range of state-of-the-art protein force fields. We construct Markov state models in order to examine the thermodynamics, kinetics, mechanism, and rate-determining step of folding. Mechanistically, we find the folding process is rate-limited by the formation of the turn region hydrogen bonds, which occurs following the downhill hydrophobic collapse of the extended denatured protein. These results are presented in the context of established and contradictory theories of the beta-hairpin folding process. Furthermore, our analysis suggests that the AMBER-FB15 force field, at this temperature, best describes the characteristics of the full experimental CLN025 conformational ensemble, while the AMBER ff99SB-ILDN and CHARMM22* force fields display a tendency to overstabilize the native state. [ABSTRACT FROM AUTHOR]

The increasing availability of high-quality experimental data and first-principles calculations creates opportunities for developing more accurate empirical force fields for simulation of proteins. We developed the AMBER-FB15 protein force field by building a high-quality quantum chemical data set consisting of comprehensive potential energy scans and employing the ForceBalance software package for parameter optimization. The optimized potential surface allows for more significant thermodynamic fluctuations away from local minima. In validation studies where simulation results are compared to experimental measurements, AMBER-FB15 in combination with the updated TIP3P-FB water model predicts equilibrium properties with equivalent accuracy, and temperature dependent properties with significantly improved accuracy, in comparison with published models. We also discuss the effect of changing the protein force field and water model on the simulation results. [ABSTRACT FROM AUTHOR]