Transferring the PRIMO Coarse-Grained Force Field to the Membrane Environment: Simulations of Membrane Proteins and Helix–Helix Association

Abstract

An extension of the recently developed PRIMO coarse-grained force field to membrane environments, PRIMO-M, is described. The membrane environment is modeled with the heterogeneous dielectric generalized Born (HDGB) methodology that simply replaces the standard generalized Born model in PRIMO without further parametrization. The resulting model was validated by comparing amino acid insertion free energy profiles and application in molecular dynamics simulations of membrane proteins and membrane-interacting peptides. Membrane proteins with 148–661 amino acids show stable root-mean-squared-deviations (RMSD) between 2 and 4 Å for most systems. Transmembrane helical peptides maintain helical shape and exhibit tilt angles in good agreement with experimental or other simulation data. The association of two glycophorin A (GpA) helices was simulated using replica exchange molecular dynamics simulations yielding the correct dimer structure with a crossing angle in agreement with previous studies. Finally, conformational sampling of the influenza fusion peptide also generates structures in agreement with previous studies. Overall, these findings suggest that PRIMO-M can be used to study membrane bound peptides and proteins and validates the transferable nature of the PRIMO coarse-grained force field.

Hybrid All-Atom/Coarse-Grained Simulations of Proteins by Direct Coupling of CHARMM and PRIMO Force Fields

“…The RMSD plot shown in Fig. 9 suggests that the AA/CG simulation is stable and comparable to previously published results with PRIMO 53 . The average C α RMSD obtained from CHARMM/PRIMO simulation was 3.2 Å while the CG simulation (PRIMO-M) yielded an average C α RMSD of 4.0 Å.…”

“…In the membrane version of PRIMO, PRIMO-M 53 , the standard GB term is simply replaced by the HDGB model 54 , and the SASA (solvent accessible surface area) term is scaled in a z- dependent fashion along the membrane normal.…”

“…In the AA/CG simulations, non-bonded interactions were cut off at 17 Å with a smooth switching to zero starting at 14 Å. However, in the case of bacteriorhodopsin, larger cutoffs of 16 and 18 Å at the beginning and end of the switching region, respectively, were used as suggested previously 53 . The non-bonded interaction list cutoff was set to 20 Å. Bacteriorhodopsin was initially placed in the membrane with its principal axis aligned with the bilayer normal ( z -axis) and its center of mass at the origin of the membrane bilayer.…”

Coarse-Grained Protein Models and Their Applications

“…The scaling of the force field has been done in a way that provides good transferability of protein systems. What is important, the PRIMO model enables productive studies of the solvent effect on protein dynamics, including simulations of membrane proteins 215 and reproducible folding simulations of small proteins.…”

“…584 Recently, Feig and co-workers presented an extension of their PRIMO coarsegrained force field onto MPs. 215 The models were positively validated by comparing amino acid insertion free energy profiles with MD simulations of MPs and membraneinteracting peptides. A versatile method for modeling membrane proteins is also available in the RosettaMP framework.…”