SIRAH: A Structurally Unbiased Coarse-Grained Force Field for Proteins with Aqueous Solvation and Long-Range Electrostatics

Abstract

Modeling of macromolecular structures and interactions represents an important challenge for computational biology, involving different time and length scales. However, this task can be facilitated through the use of coarse-grained (CG) models, which reduce the number of degrees of freedom and allow efficient exploration of complex conformational spaces. This article presents a new CG protein model named SIRAH, developed to work with explicit solvent and to capture sequence, temperature, and ionic strength effects in a topologically unbiased manner. SIRAH is implemented in GROMACS, and interactions are calculated using a standard pairwise Hamiltonian for classical molecular dynamics simulations. We present a set of simulations that test the capability of SIRAH to produce a qualitatively correct solvation on different amino acids, hydrophilic/hydrophobic interactions, and long-range electrostatic recognition leading to spontaneous association of unstructured peptides and stable structures of single polypeptides and protein-protein complexes.

The SIRAH force field 2.0: Altius, Fortius, Citius

“…Nevertheless, calculation of the total number of contacts remained nearly constant, experiencing a slight increase with sizable oscillations ( Figure 4D). The average number of inter C contacts was 58 over the last 100 ns, which is comparable to the initial value of 51, indicating that the protein-protein interface was maintained [16][17][18][19][20][21][22][23][24][25][26][27][28] despite the loss in specificity. A stringent control for this system was the coordination of Ca 2+ ions.…”

“…To ensure transferability, the new dihedral potentials V  CG , V  CG and V  CG were defined using sets of functions without repeating the same periodicity (Table 1). In addition, improper torsions were implemented to preserve their original definition in Darré et al 2015 21 and also to account for the way in which the AMBER's Leap module writes them into the topology. Regardless their definition in the parameter file, Leap only requires the central atom to be given at third position while the rest is re-sorted in alphabetical order by atom-type except for wild cards, which are placed first.…”

Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state?

“…61 The attracting interaction between domains and linker may stabilize the closed state and increase [B] 0 , while the enhanced excluded-volume (repulsive) interaction between domains and linker would decrease [B] 0 . The incorporation of these effects is straightforward by adopting other more delicate coarse-grained models, for example, the modified G o-like model with sequence-dependent hydrophobic interaction, 45,62 the SIRAH model with incorporated ion and coulomb interaction, 63,64 or Miyazawa-Jernigan-type contact potentials. 65,66 The data were derived from simulation of disordered linker (N = 60 with δ = 0.2) in four protein systems.…”

Multiscale simulation of DNA

“…The DNA model from Scheraga's group [128] was derived with the same philosophy used to derive the UNRES [153] force-field for proteins, and is expected to be compatible. Finally, the incorporation of proteins to the SIRAH force-field [154], allows the comprehensive simulation of DNA, proteins, water and ions in a multiscale (all-atom/coarsegrain) manner [125••].…”