Dataset Information

Dynamics of lipids, cholesterol, and transmembrane ?-helices from microsecond molecular dynamics simulations.

ABSTRACT: Extensive all-atom molecular dynamics (?24 ?s total) allowed exploration of configurational space and calculation of lateral diffusion coefficients of the components of a protein-embedded, cholesterol-containing model bilayer. The three model membranes are composed of an ?50/50 (by mole) dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayer and contained an ?-helical transmembrane protein (HIV-1 gp41 TM). Despite the high concentration of cholesterol, normal Brownian motion was observed and the calculated diffusion coefficients (on the order of 10(-9) cm(2)/s) are consistent with experiments. Diffusion is sensitive to a variety of parameters, and a temperature difference of ?4 K from thermostat artifacts resulted in 2-10-fold differences in diffusion coefficients and significant differences in lipid order, membrane thickness, and unit cell area. Also, the specific peptide sequence likely underlies the consistently observed faster diffusion in one leaflet. Although the simulations here present molecular dynamics (MD) an order of magnitude longer than those from previous studies, the three systems did not approach ergodicity. The distributions of cholesterol and DPPC around the peptides changed on the microsecond time scale, but not significantly enough to thoroughly explore configurational space. These simulations support conclusions of other recent microsecond MD in that even longer time scales are needed for equilibration of model membranes and simulations of more realistic cellular or viral bilayers.

SUBMITTER: Baker MK

PROVIDER: S-EPMC4254001 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Dynamics of lipids, cholesterol, and transmembrane α-helices from microsecond molecular dynamics simulations.

Baker Michelle K MK Abrams Cameron F CF

The journal of physical chemistry. B 20141118 47

Extensive all-atom molecular dynamics (∼24 μs total) allowed exploration of configurational space and calculation of lateral diffusion coefficients of the components of a protein-embedded, cholesterol-containing model bilayer. The three model membranes are composed of an ∼50/50 (by mole) dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayer and contained an α-helical transmembrane protein (HIV-1 gp41 TM). Despite the high concentration of cholesterol, normal Brownian motion was observed and ...[more]

PMID: 25380392

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Project description:BackgroundAnalysis of known protein structures reveals that identical sequence fragments in proteins can adopt different secondary structure conformations. The extent of this conformational diversity is influenced by various factors like the intrinsic sequence propensity, sequence context and other environmental factors such as pH, site directed mutations or alteration of the binding ligands. Understanding the mechanism by which the environment affects the structural ambivalence of these peptides has potential implications for protein design and reliable local structure prediction algorithms. Identification of the structurally ambivalent sequence fragments and determining the rules which dictate their conformational preferences play an important role in understanding the conformational changes observed in misfolding diseases. However, a systematic classification of their intrinsic sequence patterns or a statistical analysis of their properties and sequence context in relation to the origin of their structural diversity have largely remained unexplored.ResultsIn this work, the conformational variability of α-helices is studied by mapping sequences from the non-redundant database to identical sequences across all classes of the SCOP (Structural Classification of Proteins) database. Some helices retain their conformations when mapped in the SCOP database while others exhibit a complete/partial switch to non-helical conformations. The results clearly depict the differences in the propensities of amino acids for the variable and conserved helices. Sequences flanking these ambivalent sequence fragments have anisotropic propensities at the N- and C-termini. This structural variability is depicted by molecular dynamics simulations in explicit solvent, which show that the short conserved helices retain their conformations while their longer counterparts fray into two or more shorter helices. Variable helices in the non-redundant database exhibit a trend of retaining helical conformations while their corresponding non-helical conformations in SCOP database show large deviations from their respective initial structures by adopting partial or full helical conformations. Partially ambivalent helices are also found to retain their respective conformations.ConclusionsAll sequence fragments which show structural diversity in different proteins of the non-redundant database are investigated. The final conformation of these ambivalent sequences are dictated by a fine tuning of their intrinsic sequence propensity and the anisotropic amino acid propensity of the flanking sequences. This analysis may unravel the connection between diverse secondary structures, which conserve the overall structural fold of the protein thus determining its function.

Dataset Information

Dynamics of lipids, cholesterol, and transmembrane ?-helices from microsecond molecular dynamics simulations.

Publications

Dynamics of lipids, cholesterol, and transmembrane α-helices from microsecond molecular dynamics simulations.

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