The SIRAH 2.0 Force Field: Altius, Fortius, Citius.

Abstract

A new version of the coarse-grained (CG) SIRAH force field for proteins has been developed. Modifications to bonded and non-bonded interactions on the existing molecular topologies significantly ameliorate the structural description and flexibility of a non-redundant set of proteins. The SIRAH 2.0 force field has also been ported to the popular simulation package AMBER, which along with the former implementation in GROMACS expands significantly the potential range of users and performance of this CG force field on CPU/GPU codes. As a non-trivial example of its application, we undertook the structural and dynamical analysis of the most abundant and conserved calcium-binding protein, calmodulin (CaM). CaM is composed of two calcium-binding motifs called EF-hands, which in the presence of calcium specifically recognize a cognate peptide by embracing it. CG simulations of CaM bound to four calcium ions in the presence or absence of a binding peptide (holo and apo forms, respectively) resulted in good and stable ion coordination. The simulation of the holo form starting from an experimental structure sampled near-native conformations, retrieving quasi-atomistic precision. Removing the binding peptide enabled the EF-hands to perform large reciprocal movements, comparable to those observed in NMR structures. On the other hand, the isolated peptide starting from the helical conformation experienced spontaneous unfolding, in agreement with previous experimental data. However, repositioning the peptide in the neighborhood of one EF-hand not only prevented the peptide from unfolding but also drove CaM to a fully bound conformation, with both EF-hands embracing the cognate peptide, resembling the experimental holo structure. Therefore, SIRAH 2.0 shows the capacity to handle a number of structurally and dynamically challenging situations, including metal ion coordination, unbiased conformational sampling, and specific protein-peptide recognition.