MD Simulations of Spontaneous Membrane Protein/Detergent Micelle Formation

Abstract

The in vitro study of membrane proteins for the purpose of physicochemical analysis or structure determination often relies upon successful reconstitution into detergent micelles. Moreover, a number of biological processes such as membrane protein folding and transport rely on lipid interactions which may resemble the micellar environment. Little is known about the structures of these micelles or the processes which lead to their formation. We therefore present two 50 ns all-atom molecular dynamics simulations of spontaneous dodecylphosphocholine micelle formation around representatives of the two major families of membrane proteins, a small beta-barrel protein, OmpA, and a model alpha-helical protein, glycophorin A. Despite differences in protein architecture, we highlight common mechanistic pathways in micelle formation, which are consistent with experimental studies. We characterize the exponential kinetics of detergent-protein adsorption and suggest a simple model which may explain the aggregation process. We also compare the results with 25 and 50 ns simulations of preformed micelles containing the same proteins. We confirm that the end structures of the self-assembled micelles are similar to those from their preformed counterparts, with each micelle presenting a bilayerlike environment to the enclosed protein.

Membrane protein dynamics and detergent interactions within a crystal: A simulation study of OmpA

“…Of course, it is possible that additional (disordered) detergent molecules may be present, but not resolved, in the crystal structure. However, the integrity of the extended micellar structure of the detergent on a 50-ns timescale lends us some degree of confidence that our model of the detergent organization within the crystal is stable, as indicated by experience with, e.g., self assembly simulations of detergent͞protein micelles (18,39,40). The observed loosely packed detergent network enabled breathing motions, in agreement with the crystallographic anisotropic B factors and NMR, which were elastically propagated from larger fluctuations in the loops.…”

“…We have presented a previously undescribed MD study of a crystalline membrane protein, which complements simulations of OmpA in a bilayer (16) and micelle (17,18). This work enables comparison of membrane protein flexibility as a function of environment.…”

“…The OmpA N-terminal domain is well characterized experimentally, and simulation data are available for this protein in lipid bilayer (16) and detergent micelle (17,18) environments. The crystal unit cell used in the current simulation contains 4 OmpA molecules, 24 detergent molecules, and water (Fig.…”

Molecular dynamics investigation of the influence of anionic and zwitterionic interfaces on antimicrobial peptides’ structure: Implications for peptide toxicity and activity

“…Although simulations of peptides in DPC [16,23,38] and SDS [1,4,24,25,40,41] micelles have been carried out in the past, the current study focuses on the larger context of secondary structure induction near membrane interfaces, and the remarkable influence this has on the toxicity of antimicrobial peptides. It is also one of the most computationally intensive studies that we are aware of, with more than 200 ns of combined molecular dynamics simulations.…”

Detergent-mediated protein aggregation

“…Since then, simulations have been used to characterize the conformations and interactions of many other proteins and peptides in various detergents. While most of these studies have been initiated with a preformed detergent micelle (Wymore and Wong, 1999;Rodríguez-Ropero and Fioroni, 2012;Friemann et al, 2009;Cuthbertson et al, 2006;Lagüe et al, 2005;Khandelia and Kaznessis, 2005a,b;Löw et al, 2008;Langham et al, 2007;Chevalier et al, 2006;Patargias et al, 2005;Bond and Sansom, 2003;Khao et al, 2011;Renthal et al, 2011;Cox and Sansom, 2009;Choutko et al, 2011;Krishnamani and Lanyi, 2012;Sands et al, 2006;Psachoulia et al, 2006), simulations have also evaluated the self-assembly of detergents around a protein or peptide using atomistic (Psachoulia et al, 2006;Bond et al, 2004;Böckmann and Caflisch, 2005;Braun et al, 2004;Jalili and Akhavan, 2011) and coarse-grained (Jalili and Akhavan, 2011;Friedman and Caflisch, 2011;Bond et al, 2007; models. These simulation systems, however, have almost exclusively contained a single protein molecule or preformed dimer (or crystal lattice ).…”