Molecular Dynamics Simulations of Model Transmembrane Peptides in Lipid Bilayers: A systematic Investigation of Hydrophobic Mismatch

¹ The University of Michigan
² Univ. of Michigan

^* To whom correspondence should be addressed. E-mail: rlarson{at}umich.edu.

Submitted on August 27, 2005
Revised on October 7, 2005
Accepted on 30 December 2005

	Abstract

Hydrophobic mismatch, which is a difference between the hydrophobic length of trans-membrane segments of a protein and the hydrophobic width of the surrounding lipid bilayer, is known to play a role in membrane protein function. We have performed molecular dynamics simulations of trans-membrane KALP peptides (sequence:GKK(LA)_nLKKA) in phospholipid bilayers to investigate hydrophobic mismatch alleviation mechanisms. By varying systematically the length of the peptide (KALP₁₅, KALP₁₉, KALP₂₃, KALP₂₇ and KALP₃₁) and the lipid hydrophobic length (DLPC, DMPC and DPPC), a wide range of mismatch conditions were studied. Simulations of durations 50ns-200ns show that under positive mismatch, the system alleviates the mismatch predominantly by tilting the peptide and to a smaller extent by increased lipid ordering in the immediate vicinity of the peptide. Under negative mismatch, alleviation takes place by a combination of local bilayer bending and the "snorkeling" of the lysine residues of the peptide. Simulations performed at a higher peptide/lipid molar ratio (1:25) reveal slower dynamics of both the peptide and lipid relative to those at a lower peptide/lipid ratio (1:128). The lysine residues have favorable interactions with specific oxygen atoms of the phospholipid head groups, indicating the preferred localization of these residues at the lipid/water interface.

Key Words: Hydrophobic mismatch, KALP, Molecular Dynamics Simulations, Peptide Tilt, Snorkeling, Transmembrane peptides

This article has been cited by other articles:

				T. Carpenter, P. J. Bond, S. Khalid, and M. S. P. Sansom Self-Assembly of a Simple Membrane Protein: Coarse-Grained Molecular Dynamics Simulations of the Influenza M2 Channel Biophys. J., October 15, 2008; 95(8): 3790 - 3801. [Abstract] [Full Text] [PDF]

				U. Zimmerli and P. Koumoutsakos Simulations of Electrophoretic RNA Transport Through Transmembrane Carbon Nanotubes Biophys. J., April 1, 2008; 94(7): 2546 - 2557. [Abstract] [Full Text] [PDF]

				A. E. Daily, D. V. Greathouse, P. C. A. van der Wel, and R. E. Koeppe 2nd Helical Distortion in Tryptophan- and Lysine-Anchored Membrane-Spanning {alpha}-Helices as a Function of Hydrophobic Mismatch: A Solid-State Deuterium NMR Investigation Using the Geometric Analysis of Labeled Alanines Method Biophys. J., January 15, 2008; 94(2): 480 - 491. [Abstract] [Full Text] [PDF]

				S. Esteban-Martin and J. Salgado The Dynamic Orientation of Membrane-Bound Peptides: Bridging Simulations and Experiments Biophys. J., December 15, 2007; 93(12): 4278 - 4288. [Abstract] [Full Text] [PDF]

				W. L. Vos, M. Schor, P. V. Nazarov, R. B. M. Koehorst, R. B. Spruijt, and M. A. Hemminga Structure of Membrane-Embedded M13 Major Coat Protein Is Insensitive to Hydrophobic Stress Biophys. J., November 15, 2007; 93(10): 3541 - 3547. [Abstract] [Full Text] [PDF]

				G. Brannigan and F. L. H. Brown Contributions of Gaussian Curvature and Nonconstant Lipid Volume to Protein Deformation of Lipid Bilayers Biophys. J., February 1, 2007; 92(3): 864 - 876. [Abstract] [Full Text] [PDF]