Building a More Predictive Protein Force Field: A Systematic and Reproducible Route to AMBER-FB15

Abstract

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.

How accurately do force fields represent protein side chain ensembles?

“…Several FFs were published after 2011, which we denote as post‐2011 FFs here and of which we included following FFs in the current benchmark: GROMOS 54a7 released in 2011, CHARMM 36 from 2013, and AMBER 14SB and FB15 from 2015 and 2017, respectively. The results in Table show that for ubiquitin AMBER 14SB performs better than the older AMBER flavors, with R 2 = 0.9381 and an MAE of only 8%.…”

“…In addition, we examined 10 μs MD trajectories of both proteins simulated with AMBER 99SB‐ILDN and the TIP4P‐D water model, also provided by D. E. Shaw Research . We further performed additional 2 μs simulations with AMBER 14SB, FB15, CHARMM 36, and GROMOS 54a7 for both proteins.…”

Examination of ethanol interactions with Trp‐cage peptide through MD simulations and intermolecular nuclear Overhauser effects

“…However, while local diffusion of the water and ethanol components of the solvent near a peptide hydrogen are slowed a factor of 2 to 3 relative to diffusion in the bulk solvent, calculations done with Equation indicate that, at the RF used for our experiments (500 MHz), calculated are relatively insensitive to diffusion and that a 3‐fold change in bulk diffusion coefficient could not produce the overestimates of that are obtained from calculations with the MD trajectories. Some consideration beyond local solvent molecule diffusion seems to be required. Better agreement between observed and calculated properties of ethanol‐water solutions can be obtained by using more elaborate force fields in simulations, particularly those that include the effects of electronic polarizability . Adjustment of the parameters for the water component of these solutions may also enhance agreement …”

Molecular simulations of cellular processes

“…As highlighted in this review, the input quantities of the latter methods can be experimentally measured or calculated from detailed particle-based simulations. The second challenge will likely trigger the development of accurate force fields (Leonarski et al 2013;Ivani et al 2016;Song et al 2017;Wang et al 2017a) that are transferable to different cell conditions (Rebelo et al 2013;Parry et al 2014;Joyner et al 2016;Munder et al 2016;Sun and Fang 2016), as well as diffusion-reaction schemes (Schöneberg et al 2014;Michalski and Loew 2016;Epstein and Xu 2016) and agent-based simulations (Azimi et al 2011).…”

“…Computer simulations are often integrated with experiments performed in vivo to provide a microscopic interpretation of cellular phenomena (Hihara et al 2012;Coquel et al 2013;Di Rienzo et al 2014;Earnest et al 2017). Although powerful to predict macromolecule behavior, this technique, defined as the Bcomputational microscope^by Schulten (Lee et al 2009), has some limitations (Takada 2012;Piana et al 2014;Ivani et al 2016;Song et al 2017;Wang et al 2017a). The most challenging is the difficulty to simulate large systems represented at full atomistic resolution for timescales longer than a few μs.…”