Membrane bending is critical for the stability of voltage sensor segments in the membrane

Abstract

The interaction between membrane proteins and the surrounding membrane is becoming increasingly appreciated for its role in regulating protein function, protein localization, and membrane morphology. In particular, recent studies have suggested that membrane deformation is needed to stably accommodate proteins harboring charged amino acids in their transmembrane (TM) region, as it is energetically prohibitive to bury charge in the hydrophobic core of the bilayer. Unfortunately, current computational methods are poorly equipped for describing such deformations, as atomistic simulations are often too short to observe large-scale membrane reorganization and most continuum approaches assume a flat membrane. Previously, we developed a method that overcomes these shortcomings by using elasticity theory to characterize equilibrium membrane distortions in the presence of a TM protein, while using traditional continuum electrostatic and nonpolar energy models to determine the energy of the protein in the membrane. Here, we linked the elastostatics, electrostatics, and nonpolar numeric solvers to permit the calculation of energies for nontrivial membrane deformations. We then coupled this procedure to a robust search algorithm that identifies optimal membrane shapes for a TM protein of arbitrary chemical composition. This advance now permits us to explore a host of biological phenomena that were beyond the scope of our original method. We show that the energy required to embed charged residues in the membrane can be highly nonadditive, and our model provides a simple mechanical explanation for this nonadditivity. Our results also predict that isolated voltage sensor segments do not insert into rigid membranes, but membrane bending dramatically stabilizes these proteins in the bilayer despite their high charge content. Additionally, we use the model to explore hydrophobic mismatch with regard to nonpolar peptides and mechanosensitive channels. Our method is in quantitative agreement with molecular dynamics simulations at a tiny fraction of the computational cost.

Atomistic insight into lipid translocation by a TMEM16 scramblase

“…[15][16][17]. Briefly, a physics-based model is used that considers the energy of the protein in the membrane as the sum of three dominant terms:…”

“…The membrane deformation and its associated energy are determined by prescribing displacement and contactangle boundary conditions and solving the Euler-Lagrange equation that comes from a Helfrich-like energy functional (16,43). Further details on the continuum calculations can be found in SI Materials and Methods.…”

“…We previously developed a fast, hybrid continuum-atomistic model that treats the protein in atomistic detail, while implicitly representing the membrane using elasticity theory (15)(16)(17). Both our continuum model and MD simulations show that nhTMEM16 generates large-scale membrane deformations around the entire membrane-protein interface, including areas far away from the hydrophilic groove.…”

Antibacterial membrane attack by a pore-forming intestinal C-type lectin

“…9a-d) 17 . The model predicts that basic residues are located near the membrane-water interface while a strip of hydrophobic and polar residues is buried in the membrane core (Fig.…”

Structural and dynamic changes adopted by EmrE, multidrug transporter protein—Studies by molecular dynamics simulation

“…Such mechanism of 376 ligand recognition would be in agreement with 'vacuum cleaner' 377 hypothesis of ligand recognition by membrane protein transporters 378 from the membrane.379The ability of biological membrane components to bend is crucial to 380 understand the interaction between protein and the lipid bilayer. Ex-381 perimental and computational studies have presented that the lipid 382 molecule in membrane can bend to enable charged or polar residues 383 of proteins to be expose to the lipid headgroups[35]. An efficient com-384 putational model obtained from MD simulation of EmrE protein showed 385 that headgroup of POPE and POPG lipid molecule bends slightly to make 386 strong H-bond interaction with TYR40 and ALA96 residues, respectively 387 (Fig.…”