Conformational state‐specific free energy differences by one‐step perturbation: Protein secondary structure preferences of the GROMOS 43A1 and 53A6 force fields

Abstract

The one-step free energy perturbation approach can be applied to obtain conformational state-specific free energy differences (FEDs) associated with changes in force field parameters, and thus offers the possibility to consider conformational equilibria during force field parameterization. In this work, using the alanine decapeptide in explicit water solution as a model, the α-helical and β-hairpin state-specific FEDs associated with force field changes between two widely used parameter sets of the GROMOS force field, namely, 43A1 and 53A6, were determined using one-step perturbation. The results mostly deviated by only 1 kJ mol(−1) in absolute or a few percent in relative values from thermodynamic integration results, suggesting that the convergence ranges of one-step perturbation were large enough to cover the substantial changes in nonbonded parameters between the two parameter sets. It was also found that one-step perturbation may give larger errors when the changes from the reference state include a large decrease in van der Waals radius, as indicated by the result for the β-hairpin state-specific free energy change going from 53A6 to 43A1. According to the free energy results, the α-helical state of the alanine decapeptide is destabilized by 15 kJ mol(−1), i.e., 1.5 kJ mol(−1) per residue, relative to the β-hairpin state when going from 43A1 to 53A6, in agreement with previous direct simulations in which native α-helices were often found to be unstable in simulations using 53A6, despite that the 53A6 parameters better reproduce a range of thermodynamic properties of small molecular systems. By applying one-step perturbation to analyze the effects of perturbing individual parameters, the differential stabilization of the two secondary structure states can be traced to the changes in van der Waals parameters, especially a van der Waals parameter involved in third-neighbor interactions. This study provides an example of the efficiency of one-step perturbation in force field development, reducing the computational cost by orders of magnitude.

Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields

“…They also demonstrated that AMBER99SB*‐ILDN results in a better helix‐coil balance than AMBER99SB‐ILDN for the same peptide system . Lin et al pointed out differences in the two GROMOS96 parametrizations concerning the stabilization of α‐helical states. In fact, they showed that α‐helical states in the 43A1 parameter is approximately 15 kJ/mol more stable than in the 53A6 parameter set .…”

“…Lin et al pointed out differences in the two GROMOS96 parametrizations concerning the stabilization of α‐helical states. In fact, they showed that α‐helical states in the 43A1 parameter is approximately 15 kJ/mol more stable than in the 53A6 parameter set . Our results for these two parametrization sets correspond to these observations.…”

Investigating Ebola virus pathogenicity using molecular dynamics

“…These parameter sets are often selected in performance studies where force fields are assessed and compared [ 22 – 25 ], and where it is shown that it is still one of the best united-atom force fields available, providing in some cases even better results than some all-atom force fields. Additionally, it is known since a while that the 43A1 parameter set provides better alpha/beta relative stabilities than GROMOS parameter sets developed later [ 26 ].…”

Double phosphorylation‐induced structural changes in the signal‐receiving domain of IκBα in complex with NF‐κB

“…The simulations were carried out with Gromacs 4.5 with the modified GROMOS96 43a1p force field containing the parameters for phosphoserine. This force field was shown to give a balanced description of secondary structural elements without any bias or preference . A time step of 2 fs was used.…”