Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

Abstract

There is a small, but growing, body of literature describing the use of osmotic coefficient measurements to validate and reparameterize simulation force fields. Here we have investigated the ability of five very commonly used force field and water model combinations to reproduce the osmotic coefficients of seven neutral amino acids and five small molecules. The force fields tested include AMBER ff99SB-ILDN, CHARMM36, GROMOS54a7, and OPLS-AA, with the first of these tested in conjunction with the TIP3P and TIP4P-Ew water models. In general, for both the amino acids and the small molecules, the tested force fields produce computed osmotic coefficients that are lower than experiment; this is indicative of excessively favorable solute-solute interactions. The sole exception to this general trend is provided by GROMOS54a7 when applied to amino acids: in this case, the computed osmotic coefficients are consistently too high. Importantly, we show that all of the force fields tested can be made to accurately reproduce the experimental osmotic coefficients of the amino acids when minor modifications – some previously reported by others and some that are new to this study – are made to the van der Waals interactions of the charged terminal groups. Special care is required, however, when simulating Proline with a number of the force fields, and a hydroxyl-group specific modification is required in order to correct Serine and Threonine when simulated with AMBER ff99SB-ILDN. Interestingly, an alternative parameterization of the van der Waals interactions in the latter force field, proposed by the Nerenberg and Head-Gordon groups, is shown to immediately produce osmotic coefficients that are in excellent agreement with experiment. Overall, this study reinforces the idea that osmotic coefficient measurements can be used to identify general shortcomings in commonly used force fields’ descriptions of solute-solute interactions, and further demonstrates that modifications to van der Waals parameters provides a simple route to optimizing agreement with experiment.

Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

“…As noted earlier, Yoo & Aksimentiev have shown that increasing the σ value for the amino-carboxyl interaction fully corrects the osmotic behavior of glycine with both the AMBERff99SB-ILDN-phi and CHARMM36 force fields, 25 and we have recently shown that the same modification also improves the behavior of other amino acids. 27 In addition, we have shown that much-improved results for the same amino acids can be obtained with the GROMOS54a7 and OPLS-AA force fields by increasing or decreasing (respectively) the σ value for the same interaction. 27 …”

“…27 In addition, we have shown that much-improved results for the same amino acids can be obtained with the GROMOS54a7 and OPLS-AA force fields by increasing or decreasing (respectively) the σ value for the same interaction. 27 …”

“…Previous studies have focused on improving the behavior of a range of biomolecules such as sugars, 24, 33 and amino acids, 25–27 in addition to a variety of salts. 29–30 The present work is, to our knowledge however, the first to focus on reproducing isopiestic osmotic pressure data, and the first to describe the use of such data to reparameterize the interactions of mixed solute-solute interactions.…”

Molecular Simulations of Thermodynamic Properties for the Systemα‐Cyclodextrin/Alcohol in Aqueous Solution

“…only the thermodynamic properties used typically in the original parametrizations [101]. By considering both solubility and binding affinity on equal footing a thermodynamical consistent description of complex host-guest systems in complex solvent environments will become possible in the future.…”

Use of osmotic coefficient measurements to validate and to correct the interaction thermodynamics of amino acids in molecular dynamics simulations

“…For this thesis, over 200 simulations were performed on systems that contained approximately 10000 atoms, were simulated for at least 100 nanoseconds, and represented interactions using the state-of-the-art, fixed-charge force fields described above. [12][13] Today, biological macromolecules are regularly simulated in attempts to address these two key issues: accurately representing these macromolecules on biologically meaningful timescales and sizes. A 2014 simulation study by Petrov and Zagrovic put simulation scale and force field accuracy to the test.…”