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A solvent model for simulations of peptides in bilayers. II. Membrane-spanning alpha-helices.

ABSTRACT: We describe application of the implicit solvation model (see the first paper of this series), to Monte Carlo simulations of several peptides in bilayer- and water-mimetic environments, and in vacuum. The membrane-bound peptides chosen were transmembrane segments A and B of bacteriorhodopsin, the hydrophobic segment of surfactant lipoprotein, and magainin2. Their conformations in membrane-like media are known from the experiments. Also, molecular dynamics study of surfactant lipoprotein with different explicit solvents has been reported (Kovacs, H., A. E. Mark, J. Johansson, and W. F. van Gunsteren. 1995. J. Mol. Biol. 247:808-822). The principal goal of this work is to compare the results obtained in the framework of our solvation model with available experimental and computational data. The findings could be summarized as follows: 1) structural and energetic properties of studied molecules strongly depend on the solvent; membrane-mimetic media significantly promote formation of alpha-helices capable of traversing the bilayer, whereas a polar environment destabilizes alpha-helical conformation via reduction of solvent-exposed surface area and packing; 2) the structures calculated in a membrane-like environment agree with the experimental ones; 3) noticeable differences in conformation of surfactant lipoprotein assessed via Monte Carlo simulation with implicit solvent (this work) and molecular dynamics in explicit solvent were observed; 4) in vacuo simulations do not correctly reproduce protein-membrane interactions, and hence should be avoided in modeling membrane proteins.

SUBMITTER: Efremov RG

PROVIDER: S-EPMC1300218 | biostudies-other | 1999 May

REPOSITORIES: biostudies-other

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A solvent model for simulations of peptides in bilayers. II. Membrane-spanning alpha-helices.

Efremov R G RG Nolde D E DE Vergoten G G Arseniev A S AS

Biophysical journal 19990501 5

We describe application of the implicit solvation model (see the first paper of this series), to Monte Carlo simulations of several peptides in bilayer- and water-mimetic environments, and in vacuum. The membrane-bound peptides chosen were transmembrane segments A and B of bacteriorhodopsin, the hydrophobic segment of surfactant lipoprotein, and magainin2. Their conformations in membrane-like media are known from the experiments. Also, molecular dynamics study of surfactant lipoprotein with diff ...[more]

PMID: 10233063

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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.

Project description:We introduce here a novel Monte Carlo simulation method for studying the interactions of hydrophobic peptides with lipid membranes. Each of the peptide's amino acids is represented as two interaction sites: one corresponding to the backbone alpha-carbon and the other to the side chain, with the membrane represented as a hydrophobic profile. Peptide conformations and locations in the membrane and changes in the membrane width are sampled using the Metropolis criterion, taking into account the underlying energetics. Using this method we investigate the interactions between the hydrophobic peptide M2delta and a model membrane. The simulations show that starting from an extended conformation in the aqueous phase, the peptide first adsorbs onto the membrane surface, while acquiring an ordered helical structure. This is followed by formation of a helical-hairpin and insertion into the membrane. The observed path is in agreement with contemporary understanding of peptide insertion into biological membranes. Two stable orientations of membrane-associated M2delta were obtained: transmembrane (TM) and surface, and the value of the water-to-membrane transfer free energy of each of them is in agreement with calculations and measurements on similar cases. M2delta is most stable in the TM orientation, where it assumes a helical conformation with a tilt of 14 degrees between the helix principal axis and the membrane normal. The peptide conformation agrees well with the experimental data; average root-mean-square deviations of 2.1 A compared to nuclear magnetic resonance structures obtained in detergent micelles and supported lipid bilayers. The average orientation of the peptide in the membrane in the most stable configurations reported here, and in particular the value of the tilt angle, are in excellent agreement with the ones calculated using the continuum-solvent model and the ones observed in the nuclear magnetic resonance studies. This suggests that the method may be used to predict the three-dimensional structure of TM peptides.

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A solvent model for simulations of peptides in bilayers. II. Membrane-spanning alpha-helices.

Publications

A solvent model for simulations of peptides in bilayers. II. Membrane-spanning alpha-helices.

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