Abstract
According to the generalized conformational selection model, ligand binding involves the co-existence of at least two conformers with different ligand-affinities in a dynamical equilibrium. Conformational transitions between them should be guaranteed by intramolecular vibrational dynamics associated to each conformation. These motions are, therefore, related to the biological function of a protein. Positions whose mutations are found to alter these vibrations the most can be defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. In a previous study, we have shown that these positions are evolutionarily conserved. They correspond to buried aliphatic residues mostly localized in regular structured regions of the protein like β-sheets and α-helices. In the present paper, we perform a network analysis of these key positions for a large dataset of paired protein structures in the ligand-free and ligand-bound form. We observe that networks of interactions between these key positions present larger and more integrated networks with faster transmission of the information. Besides, networks of residues result that are robust to conformational changes. Our results reveal that the conformational diversity of proteins seems to be guaranteed by a network of strongly interconnected key positions rather than individual residues.
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References
Albert R, Jeong H, Barabasi A-L (2000) Error and attack tolerance of complex networks. Nature 406:378–382
Amitai G, Shemesh A, Sitbon E et al (2004) Network analysis of protein structures identifies functional residues. J Mol Biol 344:1135–1146
Assenov Y, Ramirez F, Schelhorn S-E et al (2008) Computing topological parameters of biological networks. Bioinformatics 24:282–284
Atilgan A, Durell S, Jernigan R et al (2001) Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys J 80:505–515
Bahar I, Erman B, Jernigan RL et al (1999) Collective motions in HIV-1 reverse transcriptase: examination of flexibility and enzyme function. J Mol Biol 285:1023–1037
Barabasi A-L, Albert R (1999) Emergence of scaling in random networks. Science 286:509–512
Bell RJ, Dean P, Hibbins-Butler DC (1970) Localization of normal modes in vitreous silica, germania and beryllium fluoride. J Phys C Solid State Phys 3:2111–2118
Bode C, Kovacs I, Szalay M et al (2007) Network analysis of protein dynamics. FEBS Lett 581:2776–2782
Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in biomolecular recognition. Nat Chem Biol 5:789–796. https://doi.org/10.1038/nchembio.232.The
Cusack MP, Thibert B, Bredesen DE, Rio G (2007) Efficient identification of critical residues based only on protein structure by network analysis. PLoS One 2:e421
Dokholyan N, Li L, Ding F, Shakhnovich E (2002) Topological determinants of protein folding. Proc Natl Acad Sci USA 99:8637–8641
Doncheva NT, Assenov Y, Domingues FS, Albrecht M (2012) Topological analysis and interactive visualization of biological networks and protein structures. Nat Protoc 7:670–685
Dos Santos HG, Abia D, Janowski R et al (2013) Structure and non-structure of centrosomal proteins. PLoS One 8:3–10
Erbel PJ, Karimi-Nejad Y, De Beer T et al (1999) Solution structure of the alpha-subunit of human chorionic gonadotropin. Eur J Biochem 260:490–498
Fajardo JE, Fiser A (2013) Protein structure based prediction of catalytic residues. BMC Bioinform 14:63
Glazer DS, Radmer RJ, Altman RB (2009) Improving structure-based function prediction using molecular dynamics. Structure 17:919–929
Gonadotropin HC, Erbel PJA, Karimi-nejad Y et al (2000) Effects of the N-linked glycans on the 3D structure of the free R-subunit of human chorionic gonadotropin. Biochemistry 39:6012–6021. https://doi.org/10.1021/bi992786n
Greene L, Higman V (2003) Uncovering network systems within protein structures. J Mol Biol 334:781–791
Hayward S, Go N (1995) Collective variable description of native protein dynamics. Annu Rev Phys Chem 46:223–250
Henzler-Wildman K, Thai V, Lei M et al (2007) Intrinsic motions along an enzymatic reaction trajectory. Nature 450:838–844
Hinsen K (1998) Analysis of domain motions by approximate normal mode calculations. Proteins Struct Funct Genet 33:417–429
Jacobs D, Rader A, Kuhn L, Thorpe M (2001) Protein flexibility predictions using graph theory. Proteins Struct Funct Genet 44:150–165
Javier Zea D, Miguel Monzon A, Fornasari MS et al (2013) Protein conformational diversity correlates with evolutionary rate. Mol Biol Evol 30:1500–1503. https://doi.org/10.1093/molbev/mst065
Jeon J, Nam HJ, Choi YS et al (2011) Molecular evolution of protein conformational changes revealed by a network of evolutionarily coupled residues. Mol Biol Evol 28:2675–2685
Jeong JI, Jang Y, Kim MK (2006) A connection rule for alpha-carbon coarse-grained elastic network models using chemical bond information. J Mol Graph Model 24:296–306
Juritz E, Fornasari MS, Martelli PL et al (2012) On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions. BMC Genomics 13(Suppl 4):S5
Juritz E, Palopoli N, Fornasari MS et al (2013) Protein conformational diversity modulates sequence divergence. Mol Biol Evol 30:79–87. https://doi.org/10.1093/molbev/mss080
Keskin O, Jernigan R, Bahar I (2000) Proteins with similar architecture exhibit similar large-scale dynamic behavior. Biophys J 78:2093–2106
Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471–505
Kitao A, Go N (1999) Investigating protein dynamics in collective coordinate space. Curr Opin Struct Biol 9:164–169
Kopito R, Ron D (2000) Conformational disease. Nat Cell Biol 2:E207–E209
Lakshminarasimhan D, Eswaramoorthy S, Burley S, Swaminathan S (2010) Structure of YqgQ protein from Bacillus subtilis, a conserved hypothetical protein. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:8–11
Lane MD, Seelig B (2014) Advances in the directed evolution of proteins. Curr Opin Chem Biol 22:129–136
Lee D, Redfern O, Orengo C (2007) Predicting protein function from sequence and structure. Nat Rev Mol Cell Biol 8:995–1005. https://doi.org/10.1038/nrm2281
Lifson S, Sander C (1979) Antiparallel and parallel beta-strands differ in amino acid residue preferences. Nature 282:109–111
Maguid S, Fernandez-Alberti S, Echave J (2008) Evolutionary conservation of protein vibrational dynamics. Gene 422:7–13
Martin AJM, Vidotto M, Boscariol F et al (2011) RING: networking interacting residues, evolutionary information and energetics in protein structures. Bioinformatics 27:2003–2005. https://doi.org/10.1093/bioinformatics/btr191
Mason O, Verwoerd M (2007) Graph theory and networks in biology. IET Syst Biol 1:89–119
Mercedes Silva M, Poland BW, Hoffman CR et al (1995) Refined crystal structures of unligated adenylosuccinate synthetase from Escherichia coli. J Mol Biol 254:431–446
Monzon AM, Juritz E, Fornasari MS, Parisi G (2013) CoDNaS: a database of conformational diversity in the native state of proteins. Bioinformatics 29:2512–2514
Monzon AM, Zea DJ, Fornasari MS et al (2016) Conformational diversity analysis reveals three functional mechanisms in proteins. PLoS Comput Biol 435:1–29. https://doi.org/10.1371/journal.pcbi.1005398
Nussinov R, Ma B (2012) Protein dynamics and conformational selection in bidirectional signal transduction. BMC Biol 10:2
Orengo CA, Michie AD, Jones S et al (1993) CATH—a hierarchic classification of protein domain structures. Structure 5:1093–1109
Parisi G, Zea DJ, Monzon AM, Marino-Buslje C (2015) Conformational diversity and the emergence of sequence signatures during evolution. Curr Opin Struct Biol 32:58–65. https://doi.org/10.1016/j.sbi.2015.02.005
Pazos F, Sternberg MJE (2004) Automated prediction of protein function and detection of functional sites from structure. Proc Natl Acad Sci USA 101:14754–14759. https://doi.org/10.1073/pnas.0404569101
Piovesan D, Minervini G, Tosatto SC (2016) The RING 2.0 web server for high quality residue interaction networks. Nucleic Acids Res 44(W1):W367–W374
Poland BW, Fromm HJ, Honzatko RB (1996) Crystal structures of adenylosuccinate synthetase from Escherichia coli complexed with GDP, IMP hadacidin, NO3 −, and Mg2+. J Mol Biol 264:1013–1027
Poland BW, Bruns C, Fromm HJ, Honzatko RB (1997) Entrapment of 6-thiophosphoryl-IMP in the active site of crystalline adenylosuccinate synthetase from Escherichia coli. J Biol Chem 272:15200–15205
Ruvinsky AM, Kirys T, Tuzikov AV, Vakser IA (2013) Ensemble-based characterization of unbound and bound states on protein energy landscape. Protein Sci 22:734–744
Saldaño T, Monzon A, Parisi G, Fernandez-Alberti S (2016) Evolutionary conserved positions define protein conformational diversity. PLoS Comput Biol 12:e1004775
Sethi A, Tian J, Derdeyn CA et al (2013) A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein. PLoS Comput Biol 9:e1003046. https://doi.org/10.1371/journal.pcbi.1003046
Sfriso P, Duran-Frigola M, Mosca R et al (2016) Residues coevolution guides the systematic identification of alternative functional conformations in proteins. Structure 24:116–126
Shannon P, Markiel A, Ozier O et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504
Slama P, Filippis I, Lappe M (2008) Detection of protein catalytic residues at high precision using local network properties. BMC Bioinform 9:517–529
Soans C, Fromm H (1991) Studies of ligand binding to Escherichia coli adenylosuccinate synthetase. Arch Biochem Biophys 310:475–480
Sol ADEL, Fujihashi H, Amoros D (2006) Residue centrality, functionally important residues, and active site shape: analysis of enzyme and non-enzyme families. Protein Sci 15:2120–2128
Tama F, Sanejouand YH (2001) Conformational change of proteins arising from normal mode calculations. Protein Eng 14:1–6
Thibert B, Bredesen DE, del Rio G (2005) Improved prediction of critical residues for protein function based on network and phylogenetic analyses. BMC Bioinform 6:213. https://doi.org/10.1186/1471-2105-6-213
Tirion MM (1996) Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys Rev Lett 77:1905–1908
Tokuriki N, Tawfik DS (2009) Protein dynamism and evolvability. Science 324:203–207. https://doi.org/10.1126/science.1169375
Vendruscolo M, Dokholyan N, Paci E, Karplus M (2002) Smallworld view of the amino acids that play a key role in protein folding. Phys Rev E 65:061910–061913
Wei G, Xi W, Nussinov R, Ma B (2016) Protein ensembles: how does nature harness thermodynamic fluctuations for life? The diverse functional roles of conformational ensembles in the cell. Chem Rev 116:6516–6551
Yang J, Roy A, Zhang Y (2013) BioLiP: a semi-manually curated database for biologically relevant ligand–protein interactions. Nucleic Acids Res 41:1096–1103. https://doi.org/10.1093/nar/gks966
Yin H, Li Y-Z, Li M-L (2011) On the relation between residue flexibility and residue interactions in proteins. Protein Pept Lett 18:450–456
Yogurtcu ON, Erdemli SB, Nussinov R et al (2008) Restricted mobility of conserved residues in protein–protein interfaces in molecular simulations. Biophys J 94:3475–3485
Yoon J, Blumer A, Lee K (2006) An algorithm for modularity analysis of directed and weighted biological networks based on edge-betweenness centrality. Bioinformatics 22:3106–3108
Zhan C, Fedorov E, Shi W et al (2005) The ybeY protein from Escherichia coli is a metalloprotein. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:959–963
Zhuravlev PI, Papoian GA (2010) Protein functional landscapes, dynamics, allostery: a tortuous path towards a universal theoretical framework. Q Rev Biophys 43:295–332. https://doi.org/10.1017/S0033583510000119
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Saldaño, T.E., Tosatto, S.C.E., Parisi, G. et al. Network analysis of dynamically important residues in protein structures mediating ligand-binding conformational changes. Eur Biophys J 48, 559–568 (2019). https://doi.org/10.1007/s00249-019-01384-1
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DOI: https://doi.org/10.1007/s00249-019-01384-1