Abstract
Cysteine (Cys) is the most important amino acid in redox biology: it is the premier residue used by proteins to maintain redox homeostasis, sense redox changes in the environment, and counteract oxidative stress. Cys is often used as a catalytic redox-active residue and plays a key role in protein structure stabilization via disulfides and metal binding. Cys is much different from other common amino acids in proteins: its unique chemical and physical properties provide high affinity for metal ions, support formation of covalent bonds with other Cys, and confer response to changes in the environment. These features are largely responsible for the broad variety of its biological functions. Thus, a better understanding of basic properties of Cys is essential for understanding the fundamental roles Cys plays in redox biology, as well as for prediction and classification of functional Cys residues in proteins. In this chapter, we provide an overview of theoretical and computational tools that have been developed in the area of thiol regulation and redox biology. In particular, we introduce and discuss methods to investigate basic properties of Cys, such as exposure and pKa, and a variety of algorithms for functional prediction of different types of Cys in proteins.
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References
Atkinson HJ, Babbitt PC (2009a) An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations. PLOS Comput Biol 5:e1000541
Atkinson HJ, Babbitt PC (2009b) Divergence of function in the thioredoxin fold suprafamily: evidence for evolution of peroxiredoxins from a thioredoxin-like ancestor. Biochemistry 48:11108–11116
Baik MH, Friesner RA (2002) Computing redox potentials in solution: density functional theory as a tool for rational design of redox agents. J Phys Chem 106:7407–7412
Beeby M, O’Connor BD, Ryttersgaard C, Boutz DR, Perry LJ, Yeates TO (2005) The genomics of disulfide bonding and protein stabilization in thermophiles. PLOS Biol 3:e309
Billiet L, Messens J, Geerlings P, Roos G (2012) The thermodynamics of thiol sulfenylation. Free Radic Biol Med 52:1473–1485
Bock A, Forchhammer K, Heider J, Baron C (1991) Selenoprotein synthesis: an expansion of the genetic code. Trends Biochem Sci 16:463–467
Brandes N, Schmitt S, Jakob U (2009) Thiol-based redox switches in eukaryotic proteins. Antioxid Redox Signal 11:997–1014
Brylinski M, Skolnick J (2011) FINDSITE-metal: integrating evolutionary information and machine learning for structure-based metal-binding site prediction at the proteome level. Proteins 79:735–751
Cabiscol E, Levine RL (1996) The phosphatase activity of carbonic anhydrase III is reversibly regulated by glutathiolation. Proc Natl Acad Sci USA 93:4170–4174
Ceroni A, Passerini A, Vullo A, Frasconi P (2006) DISULFIND: a disulfide bonding state and cysteine connectivity prediction server. Nucleic Acids Res 34:W177–W181
Chen YC, Lin YS, Lin CJ, Hwang JK (2004) Prediction of the bonding states of cysteines using the support vector machines based on multiple feature vectors and cysteine state sequences. Proteins 55:1036–1042
Cheng J, Saigo H, Baldi P (2006) Large-scale prediction of disulphide bridges using kernel methods, two-dimensional recursive neural networks, and weighted graph matching. Proteins 62:617–629
Cieplak P, Cornell WD, Bayly CI, Kollman PA (1995) Application of the multimolecule and multiconformational RESP methodology to biopolymers: charge derivation for DNA, RNA, and proteins. J Comput Chem 16:1357–1376
Copley SD, Novak WR, Babbitt PC (2004) Divergence of function in the thioredoxin fold suprafamily: evidence for evolution of peroxiredoxins from a thioredoxin-like ancestor. Biochemistry 43:13981–13995
de Castro E, Sigrist CJA, Gattiker A, Bulliard V, Langendijk-Genevaux PS, Gasteiger E, Bairoch A, Hulo N (2006) ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins. Nucleic Acids Res 34:W362–W365
Dokmanić I, Sikić M, Tomić S (2008) Metals in proteins: correlation between the metal-ion type, coordination number and the amino-acid residues involved in the coordination. Acta Crystallogr D Biol Crystallogr 64:257–263
Fermani S, Sparla F, Falini G, Martelli PL, Casadio R, Pupillo P, Ripamonti A, Trost P (2007) Molecular mechanism of thioredoxin regulation in photosynthetic A2B2-glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 104:11109–11114
Foloppe N, Sagemark J, Nordstrand K, Berndt KD, Nilsson L (2001) Structure, dynamics and electrostatics of the active site of glutaredoxin 3 from Escherichia coli: comparison with functionally related proteins. J Mol Biol 310:449–470
Fomenko DE, Gladyshev VN (2012) Comparative genomics of thiol oxidoreductases reveals widespread and essential functions of thiol-based redox control of cellular processes. Antioxid Redox Signal 16:193–201
Fomenko DE, Xing W, Adair BM, Thomas DJ, Gladyshev VN (2007) High-throughput identification of catalytic redox-active cysteine residues. Science 315:387–389
Fratelli M, Gianazza E, Ghezzi P (2004) Redox proteomics: identification and functional role of glutathionylated proteins. Expert Rev Proteomics 1:365–376
Geerlings P, De Proft F (2008) Conceptual DFT: the chemical relevance of higher response functions. Phys Chem Chem Phys 10:3028–3042
Greco TM, Hodara R, Parastatidis I, Heijnen HF, Dennehy MK, Liebler DC, Ischiropoulos H (2006) Identification of S-nitrosylation motifs by site-specific mapping of the S-nitrosocysteine proteome in human vascular smooth muscle cells. Proc Natl Acad Sci USA 103:7420–7425
Han S (2008) Force field parameters for S-nitrosocysteine and molecular dynamics simulations of S-nitrosated thioredoxin. Biochem Biophys Res Commun 377:612–616
Hao G, Derakhshan B, Shi L, Campagne F, Gross SS (2006) SNOSID, a proteomic method for identification of cysteine S-nitrosylation sites in complex protein mixtures. Proc Natl Acad Sci USA 103:1012–1017
Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674
Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS (2005) Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 62:150–166
Hook DW, Harding JJ (1997) Inactivation of glyceraldehyde 3-phosphate dehydrogenase by sugars, prednisolone-21-hemisuccinate, cyanate and other small molecules. Biochim Biophys Acta 1362:232–242
Hu H, Yang WT (2008) Free energies of chemical reactions in solution and in enzymes with ab initio quantum mechanics/molecular mechanics methods. Annu Rev Phys Chem 59:573–601
Ilbert M, Horst J, Ahrens S, Winter J, Graf PC, Lilie H, Jakob U (2007) The redox-switch domain of Hsp33 functions as dual stress sensor. Nat Struct Mol Biol 14:556–563
Iqbalsyah TM, Moutevelis E, Warwicker J, Errington N, Doig AJ (2006) The CXXC motif at the N terminus of an alpha-helical peptide. Protein Sci 15:1945–1950
Jakob U, Muse W, Eser M, Bardwell JC (1999) Chaperone activity with a redox switch. Cell 96:341–352
Jakob U, Eser M, Bardwell JC (2000) Redox switch of hsp33 has a novel zinc-binding motif. J Biol Chem 275:38302–38310
Jiang B, Tang G, Cao K, Wu L, Wang R (2010) Molecular mechanism for H(2)S-induced activation of K(ATP) channels. Antioxid Redox Signal 12:1167–11678
Jobson RW, Dehne-Garcia A, Galtier N (2010) Apparent longevity-related adaptation of mitochondrial amino acid content is due to nucleotide compositional shifts. Mitochondrion 10:540–547
Johansen D, Ytrehus K, Baxter GF (2006) Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemiareperfusion injury: evidence for a role of KATP channels. Basic Res Cardiol 101:53–60
Jordan IK, Kondrashov FA, Adzhubei IA, Wolf YI, Koonin EV, Kondrashov AS, Sunyaev S (2005) A universal trend of amino acid gain and loss in protein evolution. Nature 433:633–638
Kamerlin SC, Haranczyk M, Warshel A (2009) Progress in ab initio QM/MM free-energy simulations of electrostatic energies in proteins: accelerated QM/MM studies of pKa, redox reactions and solvation free energies. J Phys Chem B 113:1253–1272
Kim HY, Gladyshev VN (2005) Different catalytic mechanisms in mammalian selenocysteine- and cysteine-containing methionine-R-sulfoxide reductases. PLOS Biol 3:e375
Klomsiri C, Karplus PA, Poole LB (2011) Cysteine-based redox switches in enzymes. Antioxid Redox Signal 14:1065–1077
Klug A (2010) The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation. Q Rev Biophys 43:1–21
Kröncke KD, Klotz LO (2009) Zinc fingers as biologic redox switches? Antioxid Redox Signal 11:1015–1027
Kumsta C, Jakob U (2009) Redox-regulated chaperones. Biochemistry 48:4666–4676
Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21:1908–1916
Lee BC, Lobanov AV, Marino SM, Kaya A, Seravalli J, Hatfield DL, Gladyshev VN (2011) A 4-selenocysteine, 2-selenocysteine insertion sequence (SECIS) element methionine sulfoxide reductase from Metridium senile reveals a non-catalytic function of selenocysteines. J Biol Chem 286:18747–18755
Leonard SE, Reddie KG, Carroll KS (2009) Mining the thiol proteome for sulfenic acid modifications reveals new targets for oxidation in cells. ACS Chem Biol 4:783–799
Lin HH, Tseng LY (2010) DBCP: a web server for disulfide bonding connectivity pattern prediction without the prior knowledge of the bonding state of cysteines. Nucleic Acids Res 38:W503–W507
Lin CT, Lin KL, Yang CH, Chung IF, Huang CD, Yang YS (2005) Protein metal binding residue prediction based on neural networks. Int J Neural Syst 15:71–84
Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8:1419–1441
Marino SM, Gladyshev VN (2009) A structure-based approach for detection of thiol oxidoreductases and their catalytic redox-active cysteine residues. PLOS Comput Biol 5:e1000383
Marino SM, Gladyshev VN (2010a) Cysteine function governs its conservation and degeneration and restricts its utilization on protein surfaces. J Mol Biol 404:902–916
Marino SM, Gladyshev VN (2010b) Structural analysis of cysteine S-nitrosylation: a modified acid-based motif and the emerging role of trans-nitrosylation. J Mol Biol 395:844–859
Marino SM, Gladyshev VN (2011a) Redox biology: computational approaches to the investigation of functional cysteine residues. Antioxid Redox Signal 15:135–146
Marino SM, Gladyshev VN (2011b) Analysis and functional prediction of reactive cysteine residues. J Biol Chem 287:4419–4425
Mark S, Formaneck GL, Zhang X, Cui Q (2002) Calculating accurate redox potentials in enzymes with a combined QM/MM free energy perturbation approach. J Theor Comput Chem 1:53–67
Michelet L, Zaffagnini M, Vanacker H, Le Maréchal P, Marchand C, Schroda M, Lemaire SD, Decottignies P (2008) In vivo targets of S-thiolation in Chlamydomonas reinhardtii. J Biol Chem 283:21571–21578
Moosmann B (2011) Respiratory chain cysteine and methionine usage indicate a causal role for thiyl radicals in aging. Exp Gerontol 46:164–169
Moosmann B, Behl C (2008) Mitochondrially encoded cysteine predicts animal lifespan. Aging Cell 7:32–46
Nagahara N (2010) Intermolecular disulfide bond to modulate protein function as a redox-sensing switch. Amino Acids 41:59–72
Nelson KJ, Knutson ST, Soito L, Klomsiri C, Poole LB, Fetrow JS (2011) Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis. Proteins 79:947–964
Ondrechen MJ, Clifton JG, Ringe D (2001) THEMATICS: a simple computational predictor of enzyme function from structure. Proc Natl Acad Sci USA 98:12473–12478
Paget MS, Buttner MJ (2003) Thiol-based regulatory switches. Annu Rev Genet 37:91–121
Parr RG, Yang W (1995) Density-functional theory of the electronic structure of molecules. Annu Rev Phys Chem 46:701–728
Passerini A, Frasconi P (2004) Learning to discriminate between ligand-bound and disulfide-bound cysteines. Protein Eng Des Sel 17:367–373
Passerini A, Punta M, Ceroni A, Rost B, Frasconi P (2006) Identifying cysteines and histidines in transition-metal-binding sites using support vector machines and neural networks. Proteins 65:305–316
Pearson RG, Parr RG (1983) Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc 105:7512–7516
Poole LB, Karplus PA, Claiborne A (2004) Protein sulfenic acids in redox signaling. Annu Rev Pharmacol Toxicol 44:325–347
Roos G, Messens J (2011) Protein sulfenic acid formation: from cellular damage to redox regulation. Free Radic Biol Med 51:314–326
Roos G, Foloppe N, Van Laer K, Wyns L, Nilsson L, Geerlings P, Messens J (2009a) How thioredoxin dissociates its mixed disulfide. PLOS Comput Biol 5:e1000461
Roos G, Geerlings P, Messens J (2009b) Enzymatic catalysis: the emerging role of conceptual density functional theory. J Phys Chem B 113:13465–13475
Salsbury FR Jr, Knutson ST, Poole LB, Fetrow JS (2008) Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid. Protein Sci 17:299–312
Sanchez R, Riddle M, Woo J, Momand J (2008) Prediction of reversibly oxidized protein cysteine thiols using protein structure properties. Protein Sci 17:473–481
Schindeldecker M, Stark M, Behl C, Moosmann B (2011) Differential cysteine depletion in respiratory chain complexes enables the distinction of longevity from aerobicity. Mech Ageing Dev 132:171–179
Schmidt am Busch M, Knapp EW (2005) One-electron reduction potential for oxygen- and sulfur-centered organic radicals in protic and aprotic solvents. J Am Chem Soc 127:15730–15737
Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L (2005) The FoldX web server: an online force field. Nucleic Acids Res 33:W382–W388
Shenton D, Grant CM (2003) Protein S-thiolation targets glycolysis and protein synthesis in response to oxidative stress in the yeast Saccharomyces cerevisiae. Biochem J 374:513–519
Shu N, Zhou T, Hovmöller S (2008) Prediction of zinc-binding sites in proteins from sequence. Bioinformatics 24:775–782
Sigrist CJA, Cerutti L, Hulo N, Gattiker A, Falquet L, Pagni M, Bairoch A, Bucher P (2002) PROSITE: a documented database using patterns and profiles as motif descriptors. Brief Bioinform 3:265–274
Soito L, Williamson C, Knutson ST, Fetrow JS, Poole LB, Nelson KJ (2011) PREX: PeroxiRedoxin classification indEX, a database of subfamily assignments across the diverse peroxiredoxin family. Nucleic Acids Res 39:D332–D337
Tosatto SC, Bosello V, Fogolari F, Mauri P, Roveri A, Toppo S, Flohé L, Ursini F, Maiorino M (2008) The catalytic site of glutathione peroxidases. Antioxid Redox Signal 10:1515–1526
Trifonov EN (2004) The triplet code from first principles. J Biomol Struct Dyn 22:1–11
Weerapana E, Wang C, Simon GM, Richter F, Khare S, Dillon MB, Bachovchin DA, Mowen K, Baker D, Cravatt BF (2010) Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468:790–795
Winterbourn CC, Hampton MB (2008) Thiol chemistry and specificity in redox signaling. Free Radic Biol Med 45:549–561
Winterbourn CC, Metodiewa D (1999) Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radic Biol Med 27:322–328
Wood ZA, Schroder E, Robin Harris J, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci 28:32–40
Wu H, Ma BG, Zhao JT, Zhang HY (2007) How similar are amino acid mutations in human genetic diseases and evolution. Biochem Biophys Res Commun 362:233–237
Wu C, Liu T, Chen W, Oka S, Fu C, Jain MR, Parrott AM, Baykal AT, Sadoshima J, Li H (2010) Redox regulatory mechanism of transnitrosylation by thioredoxin. Mol Cell Proteomics 9:2262–2275
Xu XM, Turanov AA, Carlson BA, Yoo MH, Everley RA, Nandakumar R, Sorokina I, Gygi SP, Gladyshev VN, Hatfield DL (2010) Targeted insertion of cysteine by decoding UGA codons with mammalian selenocysteine machinery. Proc Natl Acad Sci USA 107:21430–21434
Yang G, Sun X, Wang R (2004) Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3. FASEB J 18:1782–1784
Zhang FL, Casey PJ (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65:241–269
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Marino, S.M., Roos, G., Gladyshev, V.N. (2013). Computational Redox Biology: Methods and Applications. In: Jakob, U., Reichmann, D. (eds) Oxidative Stress and Redox Regulation. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5787-5_7
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