Statistical Mechanical Model for the Transfer Free Energy of Amino Acids in the Context of Membrane Protein OmpLA

Abstract

Transfer free energy scale of amino acids is fundamental for understanding membrane protein folding and for predicting membrane protein structures. Several experimental studies have been carried out to measure the free energy of partitioning amino acids to artificial lipid bilayer or biological membranes in the context of model peptides. A recent study measured water-to-bilayer transfer free energy in the context of a native β-barrel transmembrane protein OmpLA[1]. Here we report the development of a computational free energy scale based on an empirical potential energy function and statistical mechanical model. Our energy function incorporates the energy contribution of single-body burial, inter-strand interaction and sequential nearest neighbor contact interaction. Using a statistical mechanical model with a reduced state space, we computed the full partition function of OmpLA and the relative insertion free energy of amino acids replacing Ala210. The computed relative free energy scale correlates well with experimental data (r2 =0.79 with water-to-bilayer scale[1] and r2=0.88 with translocon scale[2]). In addition, depth dependency profiles of Arg and Leu are in excellent agreement with those measured by Moon and Flemming [1]. We also obtained depth dependency profiles of all 20 amino acids which provide insight to the folding process of membrane protein. Furthermore, our model showed strong coopperativity of Arg-Arg, consistent with experimental founds[1]. We further predicted that Lys-Lys show significant cooperativity, which is subject to future experimental verification.1. Moon CP, Fleming KG (2011) Side-chain hydrophobicity scale derived from transmembrane protein folding into lipid bilayers. Proc Natl Acad Sci USA108:10174-101772. Hessa, T, Kim, H, Bihlmaier, K, Lundin, C, Boekel, J, Andersson, H, Nilsson, I, White, SH, von Heijne, G (2005). Recognition of transmembrane helices by the endoplasmic reticulum translocon. Nature, 433, 7024:377-81.