Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ₁ and χ₂ Dihedral Angles

Abstract

While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large number of applications, limitations in the model with respect to the equilibrium between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non Gly, Pro) backbone CMAP potential has been refined against experimental solution NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mechanical energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mechanical energy surfaces, followed by additional empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against data not used to guide parametrization: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equilibrium folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for the modeling and simulation studies of proteins, including studies of protein folding, assembly and functionally relevant conformational changes.

Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel

“…The final step of the series of procedures that led to a structural model consisted of ∼170 ns of equilibrated MD simulation. We used the CHARMM36 force field (25) with an applied electrical potential of -100 mV (negative on the intracellular side of the channel) and with harmonic restraints applied on the protein-backbone atoms so as to maintain a stable pore geometry. The goal of this simulation was to let the side chains relax toward their minimum free-energy conformation(s).…”

Active-site protein dynamics and solvent accessibility in nativeAchromobacter cycloclastescopper nitrite reductase

“…These were derived from the electrostatically fitted Merz-Kollman potential using a van der Waals radius of 2.0 Å for copper (Sigfridsson & Ryde, 1998), to yield formal partial electronic charges of +0.46 (T1Cu) and +1.1135 (T2Cu). The coordination sphere and geometry around the copper ions were fixed to the crystal structure and the molecular-mechanics parameters were adapted from the CHARMM36 force-field database (Best et al, 2012).…”

Energy landscape of LeuT from molecular simulations

“…32,33 Structures were equilibrated for 30 ns with harmonic constraints on the protein backbone and on substrate/Na + atoms using a force constant of 10 kcal mol −1 Å −2 for the first 10 ns and 4 kcal mol −1 Å −2 for the following by 20 ns. After this initial equilibration step, residues were substituted (from mutant to wild type), the substrate and Na + were inserted or removed depending on the initial conditions (see Table I), the system was neutralized, and a 2nd energy minimization of 20 ns with softer force constant (2 kcal mol −1 Å −2 at the same atoms) was performed to allow the systems to adapt to the introduced changes before initiating the productive runs.…”