Using one‐step perturbation to predict the effect of changing force‐field parameters on the simulated folding equilibrium of a β‐peptide in solution

Abstract

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force-field parameters. Here, we use the one-step perturbation technique to predict the change of the free enthalpy of folding of a beta-peptide in methanol solution due to changing a variety of force-field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut-off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction-field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom-positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one-step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one-step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force-field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude.

Calculation of Relative Free Energies for Ligand-Protein Binding, Solvation, and Conformational Transitions Using the GROMOS Software

“…For selected perturbations, the results were verified by performing simulations using the modified force-field parameters. The change in the free energy of folding was estimated correctly by one-step perturbation for changes in the backbone partial charges, the backbone dihedral angle energy force constants, the cutoff distance, and the dielectric permittivity of the reaction-field force . The relative perturbation free enthalpies ΔΔ G pert,R F,U = Δ G pert,R F – Δ G pert,R U for changing the backbone partial charges and the backbone dihedral angle energy force constants are shown in Figure .…”

“…Increasing the solute partial charges or backbone torsional-angle force constants leads to a stabilization of the helical fold. A perturbation involving the change of partial charges of the solvent or the entire solvent model, however, was too large to yield precise results through one-step perturbation …”

“…One-Step Perturbation. The effect of force-field changes on the folding equilibrium of a hepta-β-peptide in methanol was The Journal of Physical Chemistry B ARTICLE studied by Lin et al 37 using one-step perturbation. The method permits the estimation of the change in the free energy of folding for a variety of force-field parameter sets from a single simulation, the prediction of which would be computationally very expensive using TI or other multistep methods.…”

“…The change in the free energy of folding was estimated correctly by one-step perturbation for changes in the backbone partial charges, the backbone dihedral angle energy force constants, the cutoff distance, and the dielectric permittivity of the reaction-field force. 37 The relative perturbation free enthalpies ΔΔG pert,R F,U = ΔG pert,R F À ΔG pert,R U for changing the backbone partial charges and the backbone dihedral angle energy force constants are shown in Figure 3. Increasing the solute partial charges or backbone torsional-angle force constants leads to a stabilization of the helical fold.…”

“…A perturbation involving the change of partial charges of the solvent or the entire solvent model, however, was too large to yield precise results through one-step perturbation. 37 Enveloping Distribution Sampling. The performance of EDS was tested on a set of 10 tetrahydroisoquinoline derivatives which are inhibitors of human phenylethanolamine N-methyltransferase (PNMT).…”