,
Mark S. P. Sansom * and Alfredo Di Nola
Martin B. Ulmschneider *,
Jakob P. Ulmschneider ,
Mark S. P. Sansom * and Alfredo Di Nola
* Department of Biochemistry, University
of Oxford, Oxford, United Kingdom; and
Department of Chemistry, University of Rome "La Sapienza",
Rome, Italy
Correspondence: Address reprint requests to Martin B. Ulmschneider, Dept. of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. E-mail: martin@ulmschneider.com.
An implicit-membrane representation based
on the generalized Born theory of solvation has been
developed. The method was parameterized against the
water-to-cyclohexane insertion free energies of
hydrophobic side-chain analogs. Subsequently, the membrane
was compared with experimental data from translocon inserted
polypeptides and validated by comparison with an independent
dataset of six membrane-associated peptides and eight integral
membrane proteins of known structure and orientation.
Comparison of the insertion energy of
-helical
model peptides with the experimental values from the
biological hydrophobicity scale of Hessa et al. gave a
correlation of 93% with a mean unsigned error of 0.64
kcal/mol, when charged residues were ignored. The membrane
insertion energy was found to be dependent on residue position.
This effect is particularly pronounced for charged and
polar residues, which strongly prefer interfacial locations. All
integral membrane proteins investigated orient and insert
correctly into the implicit-membrane model. Remarkably, the
membrane model correctly predicts a partially inserted
configuration for the monotopic membrane protein
cyclooxygenase, matching experimental and theoretical
predictions. To test the applicability and usefulness of
the implicit-membrane method, molecular simulations of
influenza A M2 as well as the glycophorin A dimer were performed.
Both systems remain structurally stable and integrated into
the membrane.