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Investigation of hydrophobic moment and hydrophobicity properties for transmembrane alpha-helices.

ABSTRACT: Integral membrane proteins are the primary targets of novel drugs but are largely without solved structures. As a consequence, hydrophobic moment plot methodology is often used to identify putative transmembrane alpha-helices of integral membrane proteins, based on their local maximum mean hydrophobic moment () and the corresponding mean hydrophobicity (). To calculate these properties, the methodology identifies an optimal eleven residue window (L = 11), assuming an amino acid angular frequency, theta, fixed at 100 degrees. Using a data set of 403 transmembrane alpha-helix forming sequences, the relationship between and , and the effect of varying of L and / or theta on this relationship, was investigated. Confidence intervals for correlations between and are established. It is shown, using bootstrapping procedures that the strongest statistically significant correlations exist for small windows where 7 < or = L < or = 16. Monte Carlo analysis suggests that this correlation is dependent upon amino acid residue primary structure, implying biological function and indicating that smaller values of L give better characterisation of transmembrane sequences using . However, varying window size can also lead to different regions within a given sequence being identified as the optimal window for structure / function predictions. Furthermore, it is shown that optimal periodicity varies with window size; the optimum, based on over the range of window sizes, (7 < or = L < o= 16), was at theta = 102 degrees for the transmembrane alpha-helix data set.

SUBMITTER: Wallace J

PROVIDER: S-EPMC516255 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Investigation of hydrophobic moment and hydrophobicity properties for transmembrane alpha-helices.

Wallace James J Daman Onkabetse A OA Harris Frederick F Phoenix David A DA

Theoretical biology & medical modelling 20040816

Integral membrane proteins are the primary targets of novel drugs but are largely without solved structures. As a consequence, hydrophobic moment plot methodology is often used to identify putative transmembrane alpha-helices of integral membrane proteins, based on their local maximum mean hydrophobic moment (<microH>) and the corresponding mean hydrophobicity (<H>). To calculate these properties, the methodology identifies an optimal eleven residue window (L = 11), assuming an amino acid angula ...[more]

PMID: 15312230

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Project description:The minimum hydrophobic length necessary to form a transmembrane (TM) helix in membranes was investigated using model membrane-inserted hydrophobic helices. The fluorescence of a Trp at the center of the sequence and its sensitivity to quenching were used to ascertain helix position within the membrane. Peptides with hydrophobic cores composed of poly(Leu) were compared to sequences containing a poly 1:1 Leu:Ala core (which have a hydrophobicity typical of natural TM helices). Studies varying bilayer width revealed that the poly(Leu) core peptides predominately formed a TM state when the bilayer width exceeded hydrophobic sequence length by (i.e. when negative mismatch was) up to approximately 11-12 A (e.g. the case of a 11-12 residue hydrophobic sequence in bilayers with a biologically relevant width, i.e. dioleoylphosphatidylcholine (DOPC) bilayers), while poly(LeuAla) core peptides formed predominantly TM state with negative mismatch of up to 9 A (a 13 residue hydrophobic sequence in DOPC bilayers). This indicates that minimum length necessary to form a predominating amount of a TM state (minimum TM length) is only modestly hydrophobicity-dependent for the sequences studied here, and a formula that defines the minimum TM length as a function of hydrophobicity for moderately-to-highly hydrophobic sequences was derived. The minimum length able to form a stable TM helix for alternating LeuAla sequences, and that for sequences with a Leu block followed by an Ala block, was similar, suggesting that a hydrophobicity gradient along the sequence may not be an important factor in TM stability. TM stability was also similar for sequences flanked by different charged ionizable residues (Lys, His, Asp). However, ionizable flanking residues destabilized the TM configuration much more when charged than when uncharged. The ability of short hydrophobic sequences to form TM helices in membranes in the presence of substantial negative mismatch implies that lipid bilayers have a considerable ability to adjust to negative mismatch, and that short TM helices may be more common than generally believed. Factors that modulate the ability of bilayers to adjust to mismatch may strongly affect the configuration of short hydrophobic helices.

Dataset Information

Investigation of hydrophobic moment and hydrophobicity properties for transmembrane alpha-helices.

Publications

Investigation of hydrophobic moment and hydrophobicity properties for transmembrane alpha-helices.

Similar Datasets

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