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Titratable amino acid solvation in lipid membranes as a function of protonation state
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, Vol. 113, no 1, 245-253 p.Article in journal (Refereed) Published
Abstract [en]

Knowledge about the insertion and stabilization of membrane proteins is a key step toward understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic so as to efficiently insert into membranes, but there are many exceptions with polar or titratable residues. An obvious example is the S4 helices of voltage-gated ion channels with up to 4 arginines, leading to vivid discussion about whether such helices can insert spontaneously, and if so, what their conformation, protonation state, and cost of insertion really are. To address this question, we have determined geometric and energetic solvation properties for different protonation states of the titrateable amino acids, including hydration, side chain orientation, free energy profiles, and effects on the membrane thickness. As expected, charged states are significantly more expensive to insert (8-16 kcal/mol) than neutral variants (1-3 kcal/mol). Although both sets of values exhibit quite high relative correlation with experimental in vivo hydrophobicity scales, the magnitudes of the in vivo hydrophobicity scales are much lower and strikingly appears as a compressed version of the calculated values. This agrees well with computational studies on longer lipids but results in an obvious paradox: the differences between in vivo insertion and simulations cannot be explained by methodological differences in force fields, possible limited hydrophobic thickness of the endoplasmic reticulum (ER) membrane, or parameters; even anionic lipid head groups (PG) only have limited effect on charged side chains, and virtually none for hydrophobic ones. This leads us to propose a model for in vivo insertion that could reconcile these differences and explain the correlation: if there are considerable hydrophobic barriers inside the translocon, the experimental reference state for the solvation free energy when comparing insertion/translocation in vivo would be quite close to the bilayer environment rather than water.

Place, publisher, year, edition, pages
2009. Vol. 113, no 1, 245-253 p.
Identifiers
URN: urn:nbn:se:su:diva-27089DOI: 10.1021/jp8048873ISI: 000262167800031PubMedID: 19118487OAI: oai:DiVA.org:su-27089DiVA: diva2:212597
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2010-01-14Bibliographically 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.
Keyword
membrane protein, lipid bilayer, free energy, solvation, insertion, molecular dynamics simulations, protein mass fraction
National Category
Theoretical Chemistry
Research subject
Biochemistry
Identifiers
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)
Opponent
Supervisors
Available from: 2009-05-22 Created: 2009-05-04 Last updated: 2013-07-09Bibliographically approved

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