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Protein contents in biological membranes explain abnormal solvation of charged and polar residues
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, Vol. 106, no 37, 15684-15689 p.Article in journal (Refereed) Published
Abstract [en]

Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar or titratable residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, which enabled biological hydrophobicity scales that predict an arginine insertion cost of only 2.5 kcal/mol, compared to 14.9 kcal/mol in cyklohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to vivid discussion about the experimental conditions.  Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%. This has a striking effect on the solvation free energy of arginine, which drops more than a factor of two even for purely hydrophobic extra helices. With some polar residues present, the solvation cost comes close to experimental observation around 30% mass fraction, and negligible at 40%. The effect is mainly due to the extra helices making it easier for arginine to retain hydration water, with increasing amounts at higher protein mass fraction. These results offer a possible explanation to the previous discrepancy between the in vivo hydrophobicity scale and computer simulations, and highlight the importance of the relatively high protein contents in biological membranes. While many membrane proteins are stable in pure bilayers, the simplified models might not be sufficiently accurate descriptions of insertion for polar or charged residues in biological membranes.

Place, publisher, year, edition, pages
2009. Vol. 106, no 37, 15684-15689 p.
Keyword [en]
membrane protein, lipid bilayer, protein mass fraction, free energy, solvation, insertion, molecular dynamics simulation
URN: urn:nbn:se:su:diva-27094DOI: 10.1073/pnas.0905394106ISI: 000269806600034OAI: diva2:212610
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2010-01-18Bibliographically approved
In thesis
1. Solvation properties of proteins in membranes
Open this publication in new window or tab >>Solvation properties of proteins in membranes
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Knowledge about the insertion and stabilization of membrane proteins is a key step towards understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic to insert efficiently, but there are many exceptions with unfavorable polar or titratable residues. Since evolutionary conserved these amino acids are likely of paramount functional importance, e.g. the four arginines in the S4 voltage sensor helix of voltage-gated ion channels. This has lead to vivid discussion about their conformation, protonation state and cost of insertion. To address such questions, the main focus of this thesis has been membrane protein solvation in lipid bilayers, evaluated using molecular dynamics simulations methods.

A main result is that polar and charged amino acids tend to deform the bilayer by pulling water/head-groups into the hydrophobic core to keep their hydrogen bonds paired, thus demonstrating the adaptiveness of the membrane to allow specific and quite complex solvation. In addition, this retained hydration suggests that the solvation cost is mainly due to entropy, not enthalpy loss. To further quantify solvation properties, free energy profiles were calculated for all amino acids in pure bilayers, with shapes correlating well with experimental in vivo values but with higher magnitudes. Additional profiles were calculated for different protonation states of the titratable amino acids, varying lipid composition and with transmembrane helices present in the bilayer. While the two first both influence solvation properties, the latter seems to be a critical aspect. When the protein fraction in the models resemble biological membranes, the solvation cost drops significantly - even to values compatible with experiment.

In conclusion, by using simulation based methods I have been able to provide atomic scale explanations to experimental results, and in particular present a hypothesis for how the solvation of charged groups occurs.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2009. 62 p.
membrane protein, lipid bilayer, free energy, solvation, insertion, molecular dynamics simulations, protein mass fraction
National Category
Theoretical Chemistry
Research subject
urn:nbn:se:su:diva-27437 (URN)978-91-7155-856-5 (ISBN)
Public defence
2009-06-12, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Available from: 2009-05-22 Created: 2009-05-04 Last updated: 2013-07-09Bibliographically approved

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Johansson, Anna CVLindahl, Erik
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