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Empirical Lipid Propensities of Amino Acid Residues in Multispan Alpha Helical Membrane Proteins

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Empirical Lipid Propensities of Amino Acid Residues in Multispan Alpha Helical Membrane Proteins PROTEINS: Structure, Function, and Bioinformatics 59:496–509 (2005) Empirical Lipid Propensities of Amino Acid Residues in Multispan Alpha Helical Membrane Proteins Larisa Adamian,1 Vikas Nanda,2 William F. DeGrado,2* and Jie Liang1* 1Department of Bioengineering, University of Illinois at Chicago, Illinois 2Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ABSTRACT Characterizing the interactions be- lipid bilayer and the assembly of TM helices.1–3 The tween amino acid residues and lipid molecules is contribution from side chains interacting with their envi- important for understanding the assembly of trans- ronment reflects the energetic cost or gain due to the membrane helices and for studying membrane pro- exposure of the residue to the lipid bilayer, or to the burial tein folding. In this study we develop TMLIP (Trans- of the residue within the protein core. The contribution Membrane helix-LIPid), an empirically derived from interhelical interactions reflects the energetic cost or propensity of individual residue types to face lipid gain of various types of two-body and many-body interac- membrane based on statistical analysis of high- tions between transmembrane helices. The entropic effects resolution structures of membrane proteins. Lipid include, among other terms, the restriction of the conforma- accessibilities of amino acid residues within the tions of connected backbones and side chains. Quantitative transmembrane (TM) region of 29 structures of heli- estimation of these contributions is essential for model cal membrane proteins are studied with a spherical studies of membrane protein folding. probe of radius of 1.9 Å. Our results show that there Here we estimate the free-energy cost or gain associated are characteristic preferences for residues to face with the burial or exposure of different amino acid residue the headgroup region and the hydrocarbon core types to the lipid bilayer environment. This is an impor- region of lipid membrane. Amino acid residues Lys, tant endeavor, both for understanding the features stabi- Arg, Trp, Phe, and Leu are often found exposed at lizing membrane proteins as well as the prediction of the headgroup regions of the membrane, where they membrane protein structures. For example, an energetic have high propensity to face phospholipid head- scale for lipid exposure could be useful in differentiating groups and glycerol backbones. In the hydrocarbon core region, the strongest preference for interacting properly folded from mis-folded structures generated by with lipids is observed for Ile, Leu, Phe and Val. either ab initio or threading approaches to membrane Small and polar amino acid residues are usually protein structure prediction. Different lipid-contacting re- buried inside helical bundles and are strongly lipo- gions of a TM helix face either the highly hydrophobic phobic. There is a strong correlation between vari- hydrocarbon core or the more polar headgroup region of ous hydrophobicity scales and the propensity of a the lipid bilayer. Thus, different types of amino acid given residue to face the lipids in the hydrocarbon residues are likely to have different propensities for expo- region of the bilayer. Our data suggest a possibly sure to lipids at distinct regions of the helix–lipid inter- significant contribution of the lipophobic effect to faces. Indeed, Spencer and Rees4 showed that helical TM the folding of membrane proteins. This study shows proteins exhibit a central 20 Å-wide region with greater that membrane proteins have exceedingly apolar than 90% of its surface area contributed by carbon atoms, exteriors rather than highly polar interiors. Predic- and very few formally charged atoms. On either side of this tion of lipid-facing surfaces of boundary helices region the polarity of the protein increases in an approxi- using TMLIP1 results in a 54% accuracy, which is mately linear manner, reaching the distribution observed significantly better than random (25% accuracy). We in water-soluble proteins after another 10 Å has been also compare performance of TMLIP with another traversed. lipid propensity scale, kPROT, and with several hydrophobicity scales using hydrophobic moment analysis. Proteins 2005;59:496–509. Grant sponsor: the National Science Foundation; Grant numbers: CAREER DBI0133856 and DBI0078270; Grant sponsor: the National © 2005 Wiley-Liss, Inc. Institute of Health; Grant numbers: GM68958, HL07971-0, and GM60610. Key words: membrane protein; accessible surface; *Correspondence to: Jie Liang, Department of Bioengineering, University of Illinois at Chicago, M/C563, 835 S. Wolcott, Chicago, lipid propensity; alpha shape; hydropho- Illinois 60612-7340. E-mail: [email protected]; and William DeGrado, bicity Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Penn- INTRODUCTION sylvania 19104. E-mail: [email protected]. Received 30 July 2004; Accepted 22 December 2004 The folding of helical membrane proteins involves the Published online 23 March 2005 in Wiley InterScience burial of residues from transmembrane (TM) helices in a (www.interscience.wiley.com). DOI: 10.1002/prot.20456 © 2005 WILEY-LISS, INC. LIPID PROPENSITIES OF AMINO ACID RESIDUES 497 Lipid propensity scales can be used for prediction of angular orientation, i.e., the helix rotation that decides buried versus exposed faces of TM helices. The transfer free energy of amino acid residues from solution to differ- ent regions of the lipid bilayer has been the focus of several experimental studies5–7 that resulted in the development of the White-Wimley (WW) hydrophobicity scale, which is widely used for the prediction of TM helices in integral membrane proteins.8 There are several other well-known hydrophobicity scales that have been used for the predic- tion of TM helices in membrane proteins: Kyte-Doolittle (KD),9 Eisenberg-Weiss,10 Goldman-Engelman-Steitz,11 von Heijne,12 Rost et al.13,14 Using hydrophobicity mo- ment calculations,10,15 Rees and Eisenberg16 showed that the average hydrophobicity of the TM surface of mem- brane proteins is higher than the average hydrophobicity of the interior of soluble proteins. However, the difference in the hydrophobicity of buried and exposed residues is smaller in membrane proteins than in water-soluble pro- teins, and therefore this approach has limited success in Fig. 1. Atoms on the surface of aquaporin tetramer (1J4N) that are predicting the angular orientation of TM helices.17 To accessible to 1.9 Å probe (shown in spacefill representation). a: Top view of headgroup region. b: Top view of hydrocarbon core region. c: Side view improve the sensitivity of prediction of helical orientation, of headgroup region. d: Side view of hydrocarbon region. empirical lipid propensity scales were derived from analy- sis of membrane protein sequences18,19 or structures.20 18 Samatey et al. used the periodic distribution of residues ods. We then discuss the results and compare TMLIP with ␣ in the sequences of putative TM -helices to extract a scale several hydrophobicity scales, followed by a discussion on that describes the propensity of different amino acid predicting lipid facing surfaces of transmembrane helices. residue types to lie on the buried or exposed faces of a TM helix. This scale is limited to the central part of TM helices METHODS that faces the hydrocarbon core of the phospholipid bi- Lipid Probe Size layer. Another empirical lipid propensity scale has been Protein–lipid interactions have been studied extensively developed by Pilpel et al. from database analysis of mem- by the application of the technique of electron spin reso- brane protein sequences that takes into account the differ- nance (ESR) spectroscopy using spin-labeled phospholip- ent physico–chemical properties of the phospholipid bi- ids.22 ESR spectra showed the presence of a subpopulation layer and at the same time controls for the expected of immobilized spin labels that are not observed in protein- 19 occurrence of residues in a null model. Calculations free membrane. The interaction energy between the bound using this scale showed promising results in predicting phospholipids and membrane proteins has a broad range. lipid-facing surfaces of structures of membrane proteins. Some phospholipids transiently interact with a membrane We develop in this study a lipid propensity scale of protein, while others bind tightly to the grooves on its amino acid residues TMLIP (TM helix-LIPid) that mea- surface. To effectively sample the residues that interact sures their tendencies to partition into the core of the with phospholipids, we probe the surface of TM helices protein versus being exposed to lipids based on statistical with a sphere of radius 1.9 Å, which is the rounded up analysis of a database of structures of multispan helical value of the effective van der Waals radius of a –CH2– membrane proteins. We calculate lipid propensities sepa- group.23 The advantage of using this sphere size is that it rately for amino acid residue types in the headgroup is small enough to probe the grooved surfaces of membrane region (TMLIP-H) and in the hydrocarbon core region proteins, but large enough to have a decreased access to (TMLIP-C). These parameters help to answer important more occluded residues of the protein in comparison with a questions about membrane proteins, for example, how traditional 1.4 Å probe. Figure 1 shows in spacefilling a does the burial
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