A Continuum Method for Determining Membrane Protein Insertion Energies and the Problem of Charged Residues

Abstract

Continuum electrostatic approaches have been extremely successful at describing the charged nature of soluble proteins and how they interact with binding partners. However, it is unclear whether continuum methods can be used to quantitatively understand the energetics of membrane protein insertion and stability. Recent translation experiments suggest that the energy required to insert charged peptides into membranes is much smaller than predicted by present continuum theories. Atomistic simulations have pointed to bilayer inhomogeneity and membrane deformation around buried charged groups as two critical features that are neglected in simpler models. Here, we develop a fully continuum method that circumvents both of these shortcomings by using elasticity theory to determine the shape of the deformed membrane and then subsequently uses this shape to carry out continuum electrostatics calculations. Our method does an excellent job of quantitatively matching results from detailed molecular dynamics simulations at a tiny fraction of the computational cost. We expect that this method will be ideal for studying large membrane protein complexes.on May 9, 2018 jgp.rupress.org Downloaded from

Free-energy cost for translocon-assisted insertion of membrane proteins

“…Finally, the resulting individual insertion free energies for arginine and leucine are determined to be 6.5 kcal∕mol and −1.0 kcal∕mol, respectively. These free energies present a range that is narrower than that found in previous simulations (28,29,31,35) and is closer to the experimental one.…”

“…After accounting for the distinct hydrophobic moments of the two TM helices, i.e., ΔG 24). Both values are, however, significantly closer than those based on simulations of direct transfer of isolated amino acids from water to the membrane, which are approximately −4 kcal∕mol for leucine and þ10-14 kcal∕mol for arginine (28,29,31).…”

“…Translocation of an arginine amino acid borne by an effectively infinite polyleucine α-helix from water to the hydrophobic membrane core requires 17 kcal∕mol (27). Other studies of the translocation of side-chain analogs have corroborated the large discrepancy between computational and experimental measurements, with values ranging from 10 to 14 kcal∕mol for arginine (28)(29)(30)(31). Furthermore, the free-energy gain from the insertion of hydrophobic amino acids was also found to be consistently larger in theoretical investigations compared to experiments.…”

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:…”

“…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.…”