Accuracy of Alternate Nonpolarizable Force Fields for the Determination of Protein–Ligand Binding Affinities Dominated by Cation−π Interactions

Abstract

Modifying pair-specific Lennard-Jones parameters through the nonbonded FIX (NBFIX) feature of the CHARMM36 force field has proven cost-effective for improving the description of cation−π interactions in biological objects by means of pairwise additive potential energy functions. Here, two sets of newly optimized CHARMM36 force-field parameters including NBFIX corrections, coined CHARMM36m-NBF and CHARMM36-WYF, and the original force fields, namely CHARMM36m and Amber ff14SB, are used to determine the standard binding free energies of seven protein–ligand complexes containing cation−π interactions. Compared with precise experimental measurements, our results indicate that the uncorrected, original force fields significantly underestimate the binding free energies, with a mean error of 5.3 kcal/mol, while the mean errors of CHARMM36m-NBF and CHARMM36-WYF amount to 0.8 and 2.1 kcal/mol, respectively. The present study cogently demonstrates that the use of modified parameters jointly with NBFIX corrections dramatically increases the accuracy of the standard binding free energy of protein–ligand complexes dominated by cation−π interactions, most notably with CHARMM36m-NBF.

Meta-Analysis Reveals That Absolute Binding Free-Energy Calculations Approach Chemical Accuracy

“…Finally, 853 simulation cases from 34 different research groups (from 47 papers, i.e. , refs , − ) and from distinct schools of thought ( i.e. , routes, force fields, etc .)…”

“…For example, compared with high-throughput free-energy calculation methods, formally exact ones trade additional computational cost and human intervention for accuracy and precision, but it is undetermined whether the deal is worth it. Looking at recent papers, we notice that, on the one hand, there are a number of success stories showing free-energy calculations within chemical accuracy (error < 1 kcal/mol, coming from the typical error in thermochemical experiments), ,− while, on the other hand, some studies present estimated absolute binding affinities that differ significantly from the experimental values (error > 3 kcal/mol). , This fact makes the systematic and quantitative analysis of the reliability of free-energy calculation methods highly important.…”

Structure of SARS-CoV-2 membrane protein essential for virus assembly

“…2019.6 under periodic boundary conditions 54 – 56 . The CHARMM36m force field 57 – 61 with the WYF parameter 62 for cation-pi interactions was used. According to the default setup in the Membrane Builder, energy minimization and six equilibration runs were performed before the production run, and their calculation conditions were the same as those of our previous simulations 63 .…”

Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni

“…Updates to the force field in late 2020 attempted to rectify such issues by increasing the Lennard-Jones parameter, σ, for carboxylate-cation interactions [ 84 ]. A similar change to non-bonded parameters has been shown to improve binding affinities dominated by cation-π interactions [ 85 ]. We have used the CHARMM36m force field with these updated Lennard-Jones parameters; to our knowledge, this model is appropriate for the scope of this paper.…”