The determinants of hydrophobic mismatch response for transmembrane helices

作者：de Jesus Armando J; Allen Toby W^*

来源：Biochimica et Biophysica Acta-Biomembranes, 2013, 1828(2): 851-863.

DOI：10.1016/j.bbamem.2012.09.012

• Protein-lipid interactions
• Membrane protein
• Hydrophobic mismatch
• Molecular dynamics
• Free energy

Hydrophobic mismatch arises from a difference in the hydrophobic thickness of a lipid membrane and a transmembrane protein segment, and is thought to play an important role in the folding, stability and function of membrane proteins. We have investigated the possible adaptations that lipid bilayers and transmembrane alpha-helices undergo in response to mismatch, using fully-atomistic molecular dynamics simulations totaling 1.4 mu s. We have created 25 different tryptophan-alanine-leucine transmembrane alpha-helical peptide systems, each composed of a hydrophobic alanine-leucine stretch, flanked by 1-4 tryptophan side chains, as well as the beta-helical peptide dimer, gramicidin A. Membrane responses to mismatch include changes in local bilayer thickness and lipid order, varying systematically with peptide length. Adding more flanking tryptophan side chains led to an increase in bilayer thinning for negatively mismatched peptides, though it was also associated with a spreading of the bilayer interface. Peptide tilting, bending and stretching were systematic with tilting dominating the responses, with values of up to similar to 45 degrees for the most positively mismatched peptides. Peptide responses were modulated by the number of typtophan side chains due to their anchoring roles and distributions around the helices. Potential of mean force calculations for local membrane thickness changes, helix tilting, bending and stretching revealed that membrane deformation is the least energetically costly of all mismatch responses, except for positively mismatched peptides where helix tilting also contributes substantially. This comparison of energetic driving forces of mismatch responses allows for deeper insight into protein stability and conformational changes in lipid membranes. Published by Elsevier B.V.

• 出版日期2013-2