Refining the treatment of membrane proteins by coarse‐grained models

Abstract

Obtaining a quantitative description of the membrane proteins stability is crucial for understanding many biological processes. However the advance in this direction has remained a major challenge for both experimental studies and molecular modeling. One of the possible directions is the use of coarse-grained models but such models must be carefully calibrated and validated. Here we use a recent progress in benchmark studies on the energetics of amino acid residue and peptide membrane insertion and membrane protein stability in refining our previously developed coarse-grained model (Vicatos et al Proteins 2014; 82: 1168). Our refined model parameters were fitted and/or tested to reproduce water/membrane partitioning energetics of amino acid side chains and a couple of model peptides. This new model provides a reasonable agreement with experiment for absolute folding free energies of several β-barrel membrane proteins as well as effects of point mutations on a relative stability for one of those proteins, OmpLA. The consideration and ranking of different rotameric states for a mutated residue was found to be essential to achieve satisfactory agreement with the reference data.

Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

“…47 It also takes into account experimental polar/apolar partition coefficients. However, unlike some more recent CG models 48,49 , it has limitations, especially in consistent treatment of the electrostatic interactions. The MARTINI model is among the most frequently used CG models for biological membrane simulations.…”

A Microscopic Capacitor Model of Voltage Coupling in Membrane Proteins: Gating Charge Fluctuations in Ci-VSD

“…That is, the simple relation of Δ G rx , chem = Q g V 1/2 , 20 for nongating charge carrying mutations, offers a new avenue for estimating the relative free energies for the VSMP insertion into the membrane from the shifts in the Q – V curve. 25 This relevant free energy change, which can be induced by mutational experiments, can be examined by both using our CG model of membrane proteins (ref 31) and/or umbrella sampling enhanced (for slow degrees of freedom) all-atom molecular dynamics free energy perturbation (Bennett’s acceptance ratio). 23 …”

“…16–20 This model and its treatment of different dielectric constants is more reliable than continuum models as discussed and illustrated in many of our previous works. 31 The CG simulation system includes the protein, membrane, grids representing electrolytes, and electrode potential, virtually simulating the external voltage (see Figure 1). The residual electrolyte charge ( $q_k^g=q_k^{+}-q_k^{-}$) and the electrical potential ( φ j ) at each system grid are evaluated by solving two equations below eqs 1 and 2 in a self-consistent manner: 18 …”

“…The energetics of CG model has been constantly refined, 32 and the readers are referred to ref 31 for a recent refinement for the membrane protein system. In the present study, we only consider the electrostatic contribution ( $\mathrm{normal\Delta }{f}_{\lambda }^{\mathit{elec}}false(Vfalse)$) in great details.…”

“…20 The expression offer a new avenue to evaluate membrane-insertion free energies in voltage gated ion channels, directly from the experimental Q – V curve. 25 Alternatively, the relative shifts in the Q – V , upon site-directed mutations or drug binding, can be examined by simulating the relative free energies of mutations, using both our CG model of membrane proteins 31 and/or umbrella sampling enhanced all-atom molecular dynamics free energy perturbation (Bennett acceptance ratio). 23,52 …”