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A Generalized Born Implicit-Membrane Representation Compared to Experimental Insertion Free Energies

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{at}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.

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