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 application, we undertook the structural and dynamical analysis of the most abundant and conserved calcium-binding protein, namely, Calmodulin (CaM). CaM is constituted by two calcium-binding motifs called EF-hands, which in 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 nearnative 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 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 showed the capacity to handle a number of structurally and dynamically challenging situations including metal ion coordination, unbiased conformational sampling, and specific protein-peptide recognition.

Molecular dynamics simulations in photosynthesis

“…Marrink et al 2007;Marrink and Tieleman 2013), the SIRAH (south-American initiative for a rapid and accurate Hamiltonian) FF(Machado et al 2019), the ELBA (electrostatics-based) FF(Orsi and Essex 2011), and the SPICA FF (DeVane et al 2009; Seo and Shinoda 2019), which describe water explicitly. Other CG models like e.g., the CgProt FF(Hills et al 2010), the PLUM FF(Bereau et al 2014), or the Dry Martini FF(Arnarez et al 2015), treat the water environment implicitly.…”

Physical Interactions Driving the Activation/Inhibition of Calcium/Calmodulin Dependent Protein Kinase II

“…One of the EF hands of CaM did show a very close and stable association with the linker domain of the enzyme. This hand, which had been put initially very close to its bound position (following an analogous problem in [30]), stayed strongly associated to the region of the linker around residues T305/306, although its conformation did change, within 1 μ s, to a stable final state with an RMSD 6 Å away from the initial structure. The other EF hand, on the contrary, did not find a stable position in relation to the first hand, and freely moved in the volume between hub and kinase, making contact with residues in both of them.…”

“…The models described next are CG systems, parametrized according to the SIRAH2.0 force-field for proteins [30]. SIRAH uses three beads per aminoacid backbone, and between zero and five beads for side-chains.…”

Dissecting the role of glutamine in seeding peptide aggregation

“…This problem rapidly upscales, as different peptide sequences, multiple copies, and conditions are necessary to obtain a proper generalization in biologically relevant timescales. We circumvent these limitations by employing cutting-edge coarse-grained simulations 22 to examine glutamine's role in early aggregation events. We studied a series of polyglutamine (poly-Q) and glutamine-rich (Q-rich) peptides displaying self-aggregative behavior.…”