Abstract
Martin Bernhard Ulmschneider 1*, Mark S.P. Sansom 2 and Alfredo Di Nola 1
1 University of Rome
2
University of Oxford
To whom correspondence should be addressed.
E-mail: ulmschne@caspur.it.
Submitted on April 29, 2005
Revised on July 12, 2005
Accepted
on 13 October 2005
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Abstract |
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A computational method to calculate the orientation of membrane-associated a-helices with respect to a lipid bilayer has been developed. It is based on a previously derived implicit membrane representation, which was parameterized using the structures of 46 a-helical membrane proteins (1). The method is validated by comparison with an independent dataset of 6 trans-membrane and 9 anti-microbial peptides of known structure and orientation. The minimum energy orientations of the trans-membrane helices were found to be in good agreement with tilt and rotation angles known from solid state nuclear magnetic resonance experiments. Analysis of the free-energy landscape found two types of minima for trans-membrane peptides: i) Surface bound configurations with the helix long axis parallel to the membrane and ii) inserted configurations with the helix spanning the membrane in a perpendicular orientation. In all cases the inserted configuration also contained the global energy minimum. Repeating the calculations with a set of solution nuclear magnetic resonance structures showed that the membrane model correctly distinguishes native trans-membrane from non-native conformers. All anti-microbial peptides investigated were found to orient parallel and bind to the membrane surface in agreement with experimental data. In all cases insertion into the membrane entailed a significant free-energy penalty. An analysis of the contributions of the individual residue types confirmed that hydrophobic residues are the main driving force behind membrane protein insertion, while polar, charged and aromatic residues were found to be important for the correct orientation of the helix inside the membrane.
Key Words: alpha-helix, anti-microbial peptide, implicit membrane, nuclear magnetic resonance, potential of mean force, tilt angle