The SIRAH force field 2.0: 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. 1-28TOC. 2-28 METHODS Re-parameterization of the Model.SIRAH uses a classical Hamiltonian common to most all-atoms potentials to describe particle-particle interactions. Briefly, bonds and angles were described by harmonic terms (e.g.: k b /2*(r-r b ) 2 , with force constant k b and equilibrium values r b ), while Fourier expansions were used for dihedrals. Non-bonded contributions were accounted by Coulomb and Particle Mesh Ewald summation (PME 34,35 ), while Lennard-Jones (LJ) terms were calculated using the standard 12-6 expression (i.e.: 4**[(/r) 12 -(/r) 6 ]). Lorentz-Berthelot combination rules were used for most atom-types pairs. However, specific LJ parameters were set for tuning interactions between some bead pairs (see below). The AMBER scaling factors SCEE=1.2 and SCNB=2.0 were used for the 1-4 non-bonded interactions.3-28 7-28 22-28

Fat SIRAH: Coarse-grained phospholipids to explore membrane-protein dynamics

“…In a similar way, salt-bridge formation between lipid heads and charged amino acids was set following the same criteria used for proteins. 13 Simulated TM proteins correctly reproduced both -helical and -sheet secondary structure elements. RMSD values showed a α β well structural reproducibility, being in the range of water-soluble peptides previously reported in the last version of the force field.…”

“…A series of simulations spanning a temperature range between 303-333 K, which covers the largest portion of biological applications, showed a very good reproduction of the experimental data available in the literature. Finally, we assessed the compatibility with our recently updated force field for proteins (SIRAH 2.0) 13 by addressing the dynamics of challenging membrane proteins as the staphylococcal Alphahemolysin ( HL) heptameric pore, the bacterial outer membrane protein OmpX, the Sarco α Endoplasmic Reticulum Calcium ATPase (SERCA) and its regulator Phospholamban (PLB). We found a remarkable agreement with fundamental features reported for these proteins, as lipid dependent protein tilting, amino acid specificity for the so called "floating", "snorkeling" and "anchoring".…”

Parameterization of Divalent Cations for Coarse-Grained Simulations

“…The data presented in Figure 1 indicates that alkaline earth metals require coordination by acidic residues. Moreover, the first shell of coordination by acidic residues is entirely comprised within 0.35 nm 14 . Hence, it is safe to assume that the charge state set to +2 will not lead to severe charge unbalances in the surroundings of the protein binding site.…”

“…Indeed, even fully atomistic force fields may encounter some difficulties to properly reproduce the geometry of bound metal ions within protein binding sites without using artificial bonds 12 or dummy atoms to simulate extra charged sites 13 . Here we present a simple knowledge-based and generalizable solution to develop CG interaction parameters for divalent cations bound to proteins within the SIRAH force field (www.sirahff.com) 14 . As shown for a series of systems, this approach suffices to achieve a good structural description of metal ions bound to biologically relevant complexes, thereby avoiding the use of harmonic constraints that could alter the natural dynamics of the macromolecules.…”

From quantum to subcellular scales: multi-scale simulation approaches and the SIRAH force field

“…This choice makes the force field sensitive to point mutations and environmental conditions, like temperature, pressure, ionic strength and electric fields. In general, CG mapping is guided by physico-chemical knowledge using different bead sizes and partial charges trying to optimize intermolecular interactions needed to capture selected structural features [87].…”