kyte and doolittle hydrophobicity scale

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To avoid this circular reasoning, a naive, but effective, assumption was made: that many TM helices could be identified by a high content of the hydrophobic amino acids Ile, Leu, and Val. Acad. Res. (Fig.1,1, open circles), i.e., more hydrophobic than the most abundant hydrophobic sequences. J Mol Biol. Computational analysis of hydrophobicity is a useful method to identify transmembrane (TM) sequences in membrane proteins (Kyte and Doolittle 1982; von Heijne 1992; Claros and von Heijne 1994; Jones et al. Not every residue in a protein was scored by this approach. The complete genome sequence of. Membrane proteins under class 6 (membrane and cell surface proteins and peptides) of SCOP except the first (toxins membrane translocation domains) and the 36th folds (anthrax protective antigen) were removed. Hydrophobicity indices for amino acid residues as determined by high-performance liquid chromatography. Learn. Since no crystal structures are available for those antibodies, homology models were created using MoFvAb, as described below. Sci. Lao D.M., Arai M., Ikeda M., Shimizu T. 2002. This is . J. Chromatogr. 'H The predictive accuracy of such a scale can be improved by decreasing TM propensity values for residues enriched in the soluble sequence population and increasing TM propensity values for residues found in excess in the TM population. Protein Science : A Publication of the Protein Society, http://ecoli.aist-nara.ac.jp/gb4/FTP/ftplist.html, ftp://ftp.ncbi.nih.gov/genomes/Bacteria/Nanoarchaeum_equitans/, ftp://ftp.ncbi.nih.gov/genomes/Bacteria/Yersinia_pestis_CO92/, ftp://ftp.sanger.ac.uk/pub/yeast/pombe/Protein_data/pompep, ftp://flybase.net/genomes/Drosophila_melanogaster/current/fasta/, http://bioinfo.si.hirosaki-u.ac.jp/~TMPDB/, http://www.proteinscience.org/cgi/doi/10.1110/ps.062286306. When predicting the hydrophobicity of highly diverse antibodies, very reliable structuressuch as crystal structuresare required, while less diverse datasets can be effectively described by homology models. There are two options: you can either copy/paste your sequence into the text box or parse a FASTA or text file containing the sequence. (2000). This work was supported by the Austrian Science Fund via the grant numbers P34518, P30737, P30565, and DOC30. FOIA doi:10.1021/jp015514e. Gaussian accelerated molecular dynamics: Unconstrained enhanced sampling and free energy calculation. 1986. The effects of polar and/or ionizable residues in the core and flanking regions of hydrophobic helices on transmembrane conformation and oligomerization. Functional genomics of. Kyte-Doolittle scale.The Kyte-Doolittle scale is widely used for detecting hydrophobic regions in proteins. government site. This work adopted the K&D hy- drophobicity scale as shown in Table 2 . Biol. 4 ed. Developability assessment during the selection of novel therapeutic antibodies. 2002; Lao et al. doi:10.1073/pnas.0904191106, Chennamsetty, N., Voynov, V., Kayser, V., Helk, B., and Trout, B. L. (2010). We have shown previously that the charged amino acids form very strong enthalpic interactions with the surrounding water (Schauperl et al., 2016). The most effective scale is a new one based on fractals indicative of approach of globular curvatures to self-organized criticality, which summarizes evolutionary trends based on intelligent design. The agreement between hydrophobicity scores and HIC retention times depends strongly on the hydrophobicity scale. 79 (2), 926935. We provide an overview of the strengths and weaknesses of several commonly employed hydrophobicity scales, thereby improving the understanding of hydrophobicity in antibody development. A Perl program (genome-TM) was scripted to implement a sliding-window algorithm (Kyte and Doolittle 1982; Claros and von Heijne 1994) to analyze the amino acid sequences in the protein databases. The protein data bank. The second parameter was the fraction of TM helices not correctly identified as being TM (Pmissing TM). Prediction of physicochemical parameters by atomic contributions. PDB codes that were used for the Jain dataset. Theory Comput. 10 (7), 26772689. However, we do not claim that the TM tendency scale is the ultimate method for predicting TM helices. A 1465, 7178. 2,000 random sequences from the OAS dataset are added for comparison, with a lower opacity. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. We find that homology models generated with MoFvAb and DeepAb perform very similar in terms of predicting experimental HIC values. 1976 Oct 1;159(1):157-60. doi: 10.1042/bj1590157. 1986; Cowan and Whittaker 1990; Boyd et al. Sequences within the hydrophobicity range in which both TM and soluble sequences were abundant were used to define the soluble/TM abundance ratio (percent abundance of each amino acid in soluble sequences)/(percent abundance in TM helices). We note that the Heiden method works especially well with atomic hydrophobicity scales such as the Crippen or Eisenberg-G scale. Protein Hydrophilicity Plot. Chemical Computing Group ULC (2020). Biophysical properties of the clinical-stage antibody landscape. Kyte-Doolittle plots were first described in a paper by Kyte and Doolittle (1982). and London E. 2004. Sci. If the FASTA file has a description, it will be added to the graph as a subtitle. (1973). Hydrophobic environment is a key factor for the stability of thermophilic proteins. << 2005). (2014). This equilibrium has been observed for numerous simple hydrophobic helices in model membranes (Bechinger 1996; Ren et al. This dataset contains 127 Roche-internal antibodies for which HIC measurements of full-length IgGs have been performed. Each point represents sequences with a hydrophobicity value range from equal up to <0.05 units greater than the hydrophobicity value shown on the X-axis. We found that adding the correction factor once did not tend to fully equalize the probability that populations of soluble and TM sequences scored as having the same propensity to participate in TM helices had the same average abundance of each amino acid, and thus did not minimize misidentification of TM helices. 13 0 obj (2011). /PTEX.PageNumber 1 SCOP: A structural classification of proteins database for the investigation of sequences and structures. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Editors A. Baxevanis, G. Bader, and D. Wishart. The refinement procedure outlined above was applied to a genomic hydrophobicity scale (GH scale) we derived from a database of sequences from soluble proteins and likely TM sequences defined using genomic data (see Materials and Methods). Hydrophobicity scales are values that define the relative hydrophobicity or hydrophilicity of amino acid residues. (2017b) (called the Jain dataset below) dataset contains 127 variable domains of antibodies which were approved or undergoing clinical trials at the time of publication. Molecular operating environment (MOE). Like other hydrophobicity-type, single-value scales, TM tendency ignores factors such as the identity of neighboring residues or the depth of a residue in the bilayer (Caputo and London 2004; Hessa et al. The most frequently used scales are the hydrophobicity or hydrophilicity scales and the secondary structure conformational parameters scales, but many . Signal sequences (identified as described in Kall et al. 2001. This means that there are many differences between structures, while the SASA of each amino acid is not completely reliable. Protein Sci. A. We also show two examples of antibodies where the hydrophobicity is under-predicted compared to the experiment. Biosci. The HIC measurements from the original publication were used as reference data for this dataset. This suggests that the sampling of sidechain conformations might be better than that of global motions within the protein. This means that on the average the assigned boundaries had been correctly placed at the ends of the most hydrophobic part of the TM sequences. The ASTRAL Compendium in 2004. /BitsPerComponent 8 Two examples (mAb_17L and golimumab) are shown in Figure 7. (2011). Bethesda, MD 20894, Web Policies Retention times were compared to protein standards with known hydrophobicity. Federal government websites often end in .gov or .mil. Separation of mAbs molecular variants by analytical hydrophobic interaction chromatography HPLC Overview and applications. School of Medicine, Case Western Reserve University, United States, National Institute of Infectious Diseases (NIID), Japan. Hydrophobicity of amino-acid residues in globular-proteins. The Engelman hydrophobicity scale, also known as the GES-scale, is another scale which can be used for prediction of protein hydrophobicity [Engelman et al., 1986]. 12 (9), 46004610. This finding is consistent with the idea that protein-column interactions in HIC are dominated by the most hydrophobic surface regions (Mahn et al., 2005). 101 (1), 102115. endobj In this study we aim to compare various hydrophobicity scales and descriptors regarding their ability to predict antibody surface hydrophobicity. 19 0 obj << 2000) and Saccharomyces cerevisiae (Cherry et al. A simple method for displaying the hydropathic character of a protein. Amino acid composition of DisProt regions. Hessa T., Kim H., Bihlmaier K., Lundin C., Boekel J., Andersson H., Nilsson I., White S.H., von Heijne G. 2005. 1997). Comparison of the abundance of sequences as a function of hydrophobicity in various individual genomes as estimated by the GH scale and TM tendency scales. Notice that when the relative number of soluble sequences increases (from dash-dot-dash curve to solid curve), the hydrophobicity value at which there is a 50% probability of a sequence being a TM sequence (vertical dotted line) increases. The lack of amphiphilic sequences in the semihydrophobic range is not surprising because they should have a relatively high content of polar and ionizable residues. doi:10.1039/b927019a, PubMed Abstract | CrossRef Full Text | Google Scholar, Adelman, S. A., and Doll, J. D. (1976). To search for the abundance of (helix-type) TM sequences, the abundance of sequences having different hydrophobicity values was calculated for all proteins within a genome (as identified by open reading frames; Blattner et al. 2005). For membrane proteins there is some ambiguity concerning the assignment of the boundaries of hydrophobic TM helices. This dataset contains 77 antibodies from the dataset by Jain et al. Hydropathies listed above were taken from the Hydropathy scale derived by Kyte and Doolittle Jol Mol. We call this the equal average composition criterion. More than just the graphs. Therapeutic antibodies for autoimmunity and inflammation. SHAKE (Ryckaert et al., 1977) was used on all bonds including hydrogen. It shows that the Roche-127 set is significantly less diverse than the other datasets. We expect that this interaction region frequently coincides with a strongly hydrophobic surface region. Comparing Hydropathy scale of Kyte-Doolittle (1982) with 18 other hydropathy scales. A score of 4.6 is the most hydrophobic and a score of -4.6 is the most hydrophilic. Especially tyrosine is often found in antibody CDR regions. Thus, our computations, which assigned hydrophobicities to sequences of 19 residues and longer, would tend to report the hydrophobicity of not only the signal sequence core, but also some of the surrounding hydrophilic residues. The stratum corneum is the outermost layer and is composed of dead, keratinized cells. doi:10.1002/prot.21958. In the cases we studied, it is always better to predict HIC retention based on only the positive amino acid contributions. J. Mach. MAbs 12 (1), 1744328. doi:10.1080/19420862.2020.1744328, Gibson, T. J., Mccarty, K., Mcfadyen, I. J., Cash, E., Dalmonte, P., Hinds, K. D., et al. 1996; Kienker et al. Engelman scale. If the average hydrophobicity value for a specific sequence was equal to or above the threshold being used, then the program would mark the position as being an initial estimate for the sequence of a qualifying candidate. Evaluation of methods for measuring amino acid hydrophobicities and interactions. Instead, misidentification of TM helices was minimized when the correction factors were added twice or three times to the uncorrected values, and so this was done to define TM tendency values. Pseudo-Go values were added to scale values after adjusting them so that the size of the corrections would equal the same fraction of total hydrophobicity range as in the G-based augmented Wimley-White scale (Jayasinghe et al. 1984) indicate such helices represent a small fraction of the subhydrophobic sequences, and are not at all abundant in the semihydrophobic range, even when a low stringency hydrophobic moment is used (0.35). Hydrophobicity was calculated with a stepwise decreasing hydrophobicity threshold value. 2004) were removed from the genomic sequences. Sci. Natl. The Pearson correlation was calculated with respect to the HIC retention times of the Roche-127 dataset. Ikeda M., Arai M., Lao D.M., Shimizu T. 2002. Protonate3D: Assignment of ionization states and hydrogen coordinates to macromolecular structures. Peerj 2, e453. 1988 Sep 16;448(3):404-10. doi: 10.1016/s0021-9673(01)84603-3. 114 (5), 944949. Hydrophobic interactions of biomolecules are typically mediated by one or few hydrophobic surface patches. Jeong S.Y., Gaume B., Lee Y.J., Hsu Y.T., Ryu S.W., Yoon S.H., Youle R.J. 2004. Rev. doi:10.1016/j.cocis.2014.10.002, qvist, J., Wennerstrm, P., Nervall, M., Bjelic, S., and Brandsdal, B. O. official website and that any information you provide is encrypted 2002). Residue-based hydrophobicity scales were assigned based on the residue name. Templates were selected automatically from the built-in database, and the resulting structures were extended to FAb fragments. In the development of therapeutic antibodies, it is important to avoid problems regarding the stability, aggregation, solubility, and immunogenicity. PMC A key observation is that the intermediate hydrophobicity range defined by this method closely approximates the range in which soluble and TM sequences coexist as derived from fitting genomic data to soluble and TM protein databases (0.30.7 TM tendency values for 10% and 90% TM probabilities, respectively; see Table Table1).1). Schematic illustration of the definition of prediction accuracy as judged from the degree of overlap between hydrophobicity of soluble and TM sequences. Abanades, B., Georges, G., Bujotzek, A., and Deane, C. M. (2022). Amino acid scale values: Ala: 1.800 . A., Roberts, C. J., and Sarangapani, P. S. (2014). We therefore chose to use random initialization, but repeat the calculation 10 times and use the best embedding as judged by the Kullback-Leibler divergence (Kullback and Leibler, 1951). C~;~ajXVi9_CCr`-`C`+MkO\%g|{7Uj%pM _IqFX8cr} SI=E\u(vHuE]+5g7O`qD7hzw8BA[Xq@|\ Xp?f_ . A model recognition approach to the prediction of all-helical membrane protein structure and topology. 36 (2), 101116. We expect the CDR-H3 loop to be the most challenging part of the structure to predict. Immunol. These cavities can be, for example, binding pockets of antibodies that bind to small molecules, or they can be due to inaccurate sidechain packing in the homology models. J. Chem. The .gov means its official. A view of the hydrophobic effect. doi:10.1002/jps.22758, Lienqueo, M. E., Mahn, A., and Asenjo, J. The positive-SASA score is the same, but only taking the hydrophobic amino acids into account. 2000. 3 (10), 842848. (2017). Experimentally, the interaction of proteins with a column in Hydrophobic Interaction Chromatography (HIC) is different for proteins with homogeneous or inhomogeneous hydrophobicity profiles (Mahn et al., 2009). The enrichment is calculated and normalized over the TrEMBL database frequencies (release 2021_03). All other types were used as assigned by RDKit. This raises the possibility that a significant number of proteins have sequences that can switch between TM and non-TM states. 1A represents the consensus result of three different methods. It is composed of cells that are tightly packed together and held together by cell junctions. 9 0 obj Strohl, W. R., and Strohl, L. M. (2012). The total genomic abundance of sequences versus hydrophobicity is shown for the GH scale (open diamonds) and TM tendency (closed squares) scale for Nanoarchaeum equitans, E. coli, Y. pestis, S. cerevisiae, Schizosaccharomyces pombe, and Drosophila melanogaster. There are multiple layers in reduced enamel epithelium, which include the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. A multitude of methods have been devised to predict the hydrophobicity of antibodies in-silico. Abundance versus hydrophobicity profiles were calculated for three prokaryotic and three eukaryotic genomes. The Eisenberg scale is a normalized consensus . /Im2 28 0 R Phys. Simplified protein hydrolysis with methanesulphonic acid at elevated temperature for the complete amino acid analysis of proteins. (Fig.4)4) confirms that the TM tendency scale gives a greater degree of resolution between soluble protein and TM sequence peaks relative to the GH scale from which it was derived, with a difference in hydrophobicity values at the peaks for hydrophilic and hydrophobic proteins averaging 0.050.1 units greater for the TM tendency scale than for the GH scale. doi:10.1074/jbc.M208392200. The sum over all positive vertex scores is used to define the Heiden score. 1995, 1996; Cserzo et al. (2021). We therefore conclude that HIC measurements are controlled essentially by the most hydrophobic surface regions. Caputo G.A. Cowan R. and Whittaker R.G. The Eisenberg scale is a normalized consensus hydrophobicity . (Fig.5B5B). 1997. Blattner F.R., Plunkett G. III, Bloch C.A., Perna N.T., Burland V., Riley M., Collado-Vides J., Glasner J.D., Rode C.K., Mayhew G.F. et al. Host Plants Shape the Codon Usage Pattern of Turnip Mosaic Virus. In both cases, they lead to an increased hydrophobic surface. In the case of SAP, this is done by computing the sum of hydrophobicity values of surface-exposed side-chain atoms within a pre-defined cutoff radius (Chennamsetty et al., 2009; Chennamsetty et al., 2010). and transmitted securely. and von Heijne G. 1994. Molecular dynamics simulations of water and biomolecules with a Monte Carlo constant pressure algorithm. doi:10.1093/nar/gku399, Wang, G., Hahn, T., and Hubbuch, J. Proc. Mol. U. S. A. Mabs 13 (1). MDTraj: A modern open library for the analysis of molecular dynamics trajectories. This approach favors large hydrophobic patches, because the effect of a single hydrophobic atom can be negated by a more hydrophilic surrounding, while the values in a patch of several hydrophobic atoms add up favorably. Towards membrane protein design: pH-sensitive topology of histidine-containing polypeptides. /FormType 1 Hydrophobicity scores are then computed either by summing the surface values or by searching for patches above a certain cutoff. Soluble (solid) and TMPDB (dashed) curves schematically represent the hydrophobicity profiles of sequences in the soluble protein and TMP databases, respectively, after normalization to genomic data. Figure Figure1A1A shows that for the KD scale, the peak abundance for sequences from soluble proteins (squares) at a hydropathy/hydrophobicity value of 0.2, while that for TM sequences (circles) occurs near 1.7. doi:10.1007/s10337-017-3380-5, Bujotzek, A., Fuchs, A., Qu, C. T., Benz, J., Klostermann, S., Antes, I., et al. This means that groups of points in the embedding represent highly similar antibodies, while the distance between such groups is not necessarily representative of their similarity. (Bioinformatics explained: Protein hydrophobicity) (1984), are presented in columns 3, 4, and 5. 2004) have sequences already believed to switch between TM and non-TM states. 8600 Rockville Pike Nucleic Acids Res. A plethora of methods have been used to investigate hydrophobicity of antibodies in-silico. Membrane protein structure prediction. This shows that the TM tendency scale has an improved ability to discriminate between soluble sequences and TM helices relative to the GH scale (and thus also relative to all scales that Table Table11 shows are not as accurate as the GH scale). (1986), and Eisenberg et al. We find good correlations using hydrophobicity scales that are optimized towards HIC or other RP-HPLC data, such as the Jain or Meek scales. It is possible that there are additional cases in which predominantly soluble proteins have semihydrophobic sequences that allow formation of as-yet-undiscovered minor TM subpopulations, and vice versa. . (2021). Eisenberg D., Schwarz E., Komaromy M., Wall R. 1984. DeepAb (Ruffolo et al., 2021) was downloaded from GitHub at 3 Nov 2021, and used with PyRosetta 4 release 293 (Chaudhury et al., 2010). Natl. doi:10.1016/j.tibs.2011.08.003, Mahn, A., Lienqueo, M. E., and Salgado, J. C. (2009). Furthermore, we test several datasets, both publicly available and proprietary, and find that the diversity of the dataset affects the performance of hydrophobicity scores.
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