ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

Abstract

Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but improved secondary structure content in small peptides, and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

“…Many sampling issues have been dealt with using intensive enhanced sampling methods coupled to molecular dynamics (MD)3, 4, 5 or Monte Carlo methods 6, 7. However, the issues associated with potential energy function or force field accuracy are substantially more problematic and remain a major challenge in force field development and molecular recognition applications 8, 9…”

“…Within the range of fixed‐point‐charge, pairwise additive MM force fields available for molecular simulation,8, 10, 11, 12, 13, 14, 15, 16, 17 a number of philosophies exist for the derivation of atomic partial charges and calculation of electrostatic interactions. These models often take account of polarization implicitly in the derivation of charges, and are mainly parameterized to recreate interactions in the aqueous phase.…”

Oxetane Grafts Installed Site‐Selectively on Native Disulfides to Enhance Protein Stability and Activity In Vivo

“…The improvement of binding activity is a considerable advantage of the incorporation of the oxetane graft when compared, for instance, with the recently reported methylene thioacetal that led to a decrease in binding affinity to SSTR2 3b. Interestingly, 0.5 μs MD simulations performed on these derivatives in explicit water and using ff14SB amber force‐field15 suggested that octreotide 4 and its stapled derivative 5 presented a similar conformational behavior in solution (Figure 2 d; Supporting Information, Figure S8),16 displaying an equilibrium between antiparallel β‐sheet structures and conformations in which the C‐terminal residues form a 3 10 helix‐like fold, as reported in DMSO solution. In contrast, stapled somatostatin 3 was more rigid and displayed a more defined conformation in solution than 2 (Figure 2 c; Supporting Information, Figures S6 and S7) 17.…”

An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function

“…39,40 The complex models of WT / H130R T2-TrpRS bound with EC1-2 domain of chicken VE-cadherin were independently immersed into the center of a truncated octahedron box of TIP3P water molecules with a margin distance of 12.0 Å, potassium counterions were added by using the AMBER XLEAP module to keep system in electric neutrality. 39 Each binding complex was firstly energy minimized by the steepest descent method for 2000 steps with WT / H130R T2-TrpRS and EC1-2 restricted by a harmonic constraint of 100 kcal·mol −1 Å −2 .…”