A Method to Assess Correct/Misfolded Structures of Transmembrane Domains of Membrane Proteins (original) (raw)
Related papers
Journal of Chemical Information and Modeling, 2007
Integral membrane proteins (MPs) are pharmaceutical targets of exceptional importance. Modern methods of three-dimensional protein structure determination often fail to supply the fast growing field of structurebased drug design with the requested MPs' structures. That is why computational modeling techniques gain a special importance for these objects. Among the principal difficulties limiting application of these methods is the low quality of the MPs' models built in silico. In this series of two papers we present a computational approach to the assessment of the packing "quality" of transmembrane (TM) R-helical domains in proteins. The method is based on the concept of protein environment classes, whereby each amino acid residue is described in terms of its environment polarity and accessibility to the membrane. In the first paper we analyze a nonredundant set of 26 TM R-helical domains and compute the residues' propensities to five predefined classes of membrane-protein environments. Here we evaluate the proposed approach only by various test sets, cross-validation protocols and ability of the method to delimit the crystal structure of visual rhodopsin, and a number of its erroneous theoretical models. More advanced validation of the method is given in the second article of this series. We assume that the developed "membrane score" method will be helpful in optimizing computer models of TM domains of MPs, especially G-protein coupled receptors.
A novel method for packing quality assessment of transmembrane α-helical domains in proteins
Biochemistry (Moscow), 2007
Integral membrane proteins (MPs) are of exception al biological importance; they are known to mediate transmembrane (TM) signal transduction, light absorp tion, generation of TM potential, etc. For example, G protein coupled receptors (GPCR), the broadest and most important class of MPs, are targets for more than 50% of all currently marketed drugs [1] since their malfunction is connected to a number of diseases . The functioning of MPs depends primarily on the TM domain, which often binds a ligand and accommodates conformational reorga nization initiating intracellular response. Information on the structure and functioning of TM domains is urgently required for pharmaceutical applications, such as struc ture based drug design. Modern experimental techniques of three dimensional (3D) structure determination, such as X ray crystallography and NMR spectroscopy, on the other hand, often fail to solve the problem due to techni cal difficulties related to protein purification and crystal lization . Only a few tens of MP structures have been Abstract-Here we present a novel method for assessment of packing quality for transmembrane (TM) domains of α heli cal membrane proteins (MPs), based on analysis of available high resolution experimental structures of MPs. The present ed concept of protein membrane environment classes permits quantitative description of packing characteristics in terms of membrane accessibility and polarity of the nearest protein groups. We demonstrate that the method allows identification of native like conformations among the large set of theoretical MP models. The developed "membrane scoring function" will be of use for optimization of TM domain packing in theoretical models of MPs, first of all G protein coupled receptors.
Determining membrane protein structures: still a challenge!
Trends in Biochemical Sciences, 2007
Determination of structures and dynamics events of transmembrane proteins is important for the understanding of their function. Analysis of such events requires high-resolution 3D structures of the different conformations coupled with molecular dynamics analyses describing the conformational pathways. However, the solution of 3D structures of transmembrane proteins at atomic level remains a particular challenge for structural biochemists-the need for purified and functional transmembrane proteins causes a 'bottleneck'. There are various ways to obtain 3D structures: X-ray diffraction, electron microscopy, NMR and modelling; these methods are not used exclusively of each other, and the chosen combination depends on several criteria. Progress in this field will improve knowledge of ligand-induced activation and inhibition of membrane proteins in addition to aiding the design of membrane-protein-targeted drugs. Purification and characterization Because TMPs comprise a hydrophobic core inserted into the lipid bilayer and hydrophilic domains on either side of Review
Protein Science, 2001
The Profiles-3D application, an inverse-folding methodology appropriate for water-soluble proteins, has been modified to allow the determination of structural properties of integral-membrane proteins (IMPs) and for testing the validity of solved and model structures of IMPs. The modification, known as reverse-environment prediction of integral membrane protein structure (REPIMPS), takes into account the fact that exposed areas of side chains for many residues in IMPs are in contact with lipid and not the aqueous phase. This (1) allows lipid-exposed residues to be classified into the correct physicochemical environment class, (2) significantly improves compatibility scores for IMPs whose structures have been solved, and (3) reduces the possibility of rejecting a three-dimensional structure for an IMP because the presence of lipid was not included. Validation tests of REPIMPS showed that it (1) can locate the transmembrane domain of IMPs with single transmembrane helices more frequently than a range of other methodologies, (2) can rotationally orient transmembrane helices with respect to the lipid environment and surrounding helices in IMPs with multiple transmembrane helices, and (3) has the potential to accurately locate transmembrane domains in IMPs with multiple transmembrane helices. We conclude that correcting for the presence of the lipid environment surrounding the transmembrane segments of IMPs is an essential step for reasonable modeling and verification of the three-dimensional structures of these proteins.
ChemInform, 2007
We describe a set of tests designed to check the ability of the new "membrane score" method (see the first paper of this series) to assess the packing quality of transmembrane (TM) R-helical domains in proteins. The following issues were addressed: (1) Whether there is a relation between the score (S mem) of a model and its closeness to the "nativelike" conformation? (2) Is it possible to recognize a correct model among misfolded and erroneous ones? (3) To what extent the score of a homology-built model is sensitive to errors in sequence alignment? To answer the first question, two test cases were considered: (i) Several models of bovine aquaporin-1 (target protein) were built on the structural templates provided by its homologs with known X-ray structure. (ii) Side chains in the spatial models of visual rhodopsin and cytochrome c oxidase were rebuilt based on the backbone scaffolds taken from their crystal structures, and the resulting models were iteratively fitted into the full-atom X-ray conformations. It was shown that the higher the S mem value of a model is, the lower its root-mean-square deviation is from the "correct" (crystal) structure of a target. Furthermore, the "membrane score" method successfully identifies the rhodopsin crystal structure in an ensemble of "rotamer-type" decoys, thus providing the way to optimize mutual orientations of R-helices in models of TM domains. Finally, being applied to a set of homology models of rhodopsin built on its crystal structure with systematically shifted alignment, the approach demonstrates a prominent ability to detect alignment errors. We therefore assume that the "membrane score" method will be helpful in optimization of in silico models of TM domains in proteins, especially those in GPCRs.
Bioinformatics, 2004
The dearth of structural data on α-helical membrane proteins (MPs) has hampered thus far the development of reliable knowledge-based potentials that can be used for automatic prediction of transmembrane (TM) protein structure. While algorithms for identifying TM segments are available, modeling of the TM domains of α-helical MPs involves assembling the segments into a bundle. This requires the correct assignment of the buried and lipid-exposed faces of the TM domains. Results: A recent increase in the number of crystal structures of α-helical MPs has enabled an analysis of the lipid-exposed surfaces and the interiors of such molecules on the basis of structure, rather than sequence alone. Together with a conservation criterion that is based on previous observations that conserved residues are mostly found in the interior of MPs, the bias of certain residue types to be preferably buried or exposed is proposed as a criterion for predicting the lipid-exposed and interior faces of TMs. Applications to known structures demonstrates 80% accuracy of this prediction algorithm. Availability: The algorithm used for the predictions is implemented in the ProperTM Web server
A novel method for packing quality assessment of transmembrane alpha-helical domains in proteins
Biochemistry. Biokhimii͡a, 2007
Here we present a novel method for assessment of packing quality for transmembrane (TM) domains of alpha-helical membrane proteins (MPs), based on analysis of available high-resolution experimental structures of MPs. The presented concept of protein-membrane environment classes permits quantitative description of packing characteristics in terms of membrane accessibility and polarity of the nearest protein groups. We demonstrate that the method allows identification of native-like conformations among the large set of theoretical MP models. The developed "membrane scoring function" will be of use for optimization of TM domain packing in theoretical models of MPs, first of all G-protein coupled receptors.
An empirical energy function for structural assessment of protein transmembrane domains
Biochimie, 2015
Knowing the structure of a protein is essential to characterize its function and mechanism at the molecular level. Despite major advances in solving structures experimentally, most membrane protein native conformations remain unknown. This lack of available structures, along with the physical constraints imposed by the lipid bilayer environment, constitutes a difficulty for the modelling of membrane protein structures. Assessing the quality of membrane protein models is therefore critical. Using a non-redundant set of 66 membrane protein structures (41 alpha and 25 beta), we have developed an empirical energy function for the structural assessment of alpha-helical and beta-sheet transmembrane domains. This statistical potential quantifies the interatomic distance between residues located in the lipid bilayer. To minimize the problem of insufficient sampling, we have used kernel density estimations of the distance distributions. Following a leave-one-out cross-validation procedure, we show that our method outperforms current statistical potentials in discriminating correct from incorrect membrane protein models. Furthermore, the comparison of our distance-dependent statistical potential with one optimized on globular proteins provides insights into the rules by which residues interact within the lipid bilayer.
Bioinformatics (Oxford, England), 2016
The experimental determination of membrane protein orientation within the lipid bilayer is extremely challenging, such that computational methods are most often the only solution. Moreover, obtaining all-atom 3D structures of membrane proteins is also technically difficult, and many of the available data are either experimental low-resolution structures or theoretical models, whose structural quality needs to be evaluated. Here, to address these two crucial problems, we propose OREMPRO, a web server capable of both (i) positioning a-helical and b-sheet transmembrane domains in the lipid bilayer and (ii) assessing their structural quality. Most importantly, OREMPRO uses the sole alpha carbon coordinates, which makes it the only web server compatible with both high and low structural resolutions. Finally, OREMPRO is also interesting in its ability to process coarse-grained protein models, by using coordinates of backbone beads in place of alpha carbons.
Febs Journal, 2007
α-Helical integral-membrane proteins (IMPs) play a key role in many biological processes, such as signal transduction, and are targets for >50% of current therapeutic drugs. In contrast to their significant abundance and biological importance, they comprise <1% of structurally solved proteins. In the absence of experimental evidence, molecular modeling of IMP structures is an alternative for providing structural information and aiding further experimental design. In the current work, we propose two new amino acid lipid-facing propensity scales derived from the structural analysis of a nonredundant set of water-soluble proteins. The new scales, π and δ, perform as well or better than published scales (Carugo's hydrophobicity and kPROT scales) in predicting the lipid-facing side of helical segments of a set of structurally solved IMPs, thus indicating (a) that the folding properties of water-soluble proteins and IMPs are similar, and (b) that the new scales will prove useful in modeling the transmembrane segments of IMPs.