A generalized Born implicit membrane representation compared to experimental insertion free energies

¹ University of Oxford
² University of Rome

^* To whom correspondence should be addressed. E-mail: ulmschne{at}caspur.it.

Submitted on January 24, 2006
Revised on February 25, 2006
Accepted on 20 December 2006

	Abstract

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 against experimental data from translocon inserted polypeptides and validated by comparison with an independent dataset of 6 membrane associated peptides and 8 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. (1) 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. In order to test the applicability and usefulness of the implicit membrane method molecular simulations of Influenza A as well as the Glycophorin A dimer were performed. Both systems remain structurally stable and integrated into the membrane.

Key Words: biological hydrophobicity scale, generalized born, implicit membrane, membrane protein, monte carlo

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