Chemical Functionality of the Aqueous Interface in Soluble Proteins

  • Ariel Fernández Stigliano


Building upon a non-Debye multiscale treatment of water dielectrics, this chapter reveals the chemical functionality of biomolecular interfaces. More specifically, it asserts the chemical basicity of interfacial water enveloping nanoscale structural defects (dehydrons) in soluble proteins and establishes the participation of dehydrons in biochemical events. The quasi-reactant status of dehydrons is already implied by their significant concentration in the vicinity of an enzymatically active site, delineating their role as promoters or enhancers of catalytic activity. We further delineate the enabling role of dehydrons as activators of nucleophilic groups engaged in catalysis. This activation results from the induction of chemical basicity in interfacial water molecules, promoting deprotonation of adjacent nucleophiles. Through multiple steering molecular dynamics with pulling along the proton-displacement coordinate, we show that nucleophilic groups are functionally enabled by nearby dehydrons. The computations are validated against experimentally evidence on specific pKa decreases at functional sites and on degenerative deregulation of catalytic activity arising from dehydron-generating mutations. The proton-acceptor role of dehydrons, or rather, of interfacial water enveloping dehydrons, is likely to revolutionize our understanding of biochemical mechanism. It is probable that most if not all transesterification reactions in biochemistry requiring the activation of a nucleophilic group will need to be rewritten to incorporate the catalytic enablement provided by nearby dehydrons. A new biochemical quasi-reactant has been thus discovered demanding a vast revision of the mechanistic literature in bio-organic chemistry.


Interfacial Water Proton Acceptor Chemical Functionality Nucleophilic Group Aqueous Interface 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Fernández A (2013) The principle of minimal episteric distortion of the water matrix and its steering role in protein folding. J Chem Phys 139:085101CrossRefPubMedGoogle Scholar
  2. 2.
    Giovambattista N, Lopez CF, Rossky P, Debenedetti P (2008) Hydrophobicity of protein surfaces: separating geometry from chemistry. Proc Natl Acad Sci USA 105:2274–2279CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Fernández A (2012) Epistructural tension promotes protein associations. Phys Rev Lett 108:188102CrossRefPubMedGoogle Scholar
  4. 4.
    Kumar P, Han S, Stanley HE (2009) Anomalies of water and hydrogen bond dynamics in hydrophobic nanoconfinement. J Phys Condens Matter 21:504108CrossRefPubMedGoogle Scholar
  5. 5.
    Schutz CN, Warshel A (2001) What are the dielectric “constants” of proteins and how to validate electrostatic models? Proteins-Struct Funct Gen 44:400–408CrossRefGoogle Scholar
  6. 6.
    Fernández A (2014) Communication: chemical functionality of interfacial water enveloping nanoscale structural defects in proteins. J Chem Phys 140:221102CrossRefPubMedGoogle Scholar
  7. 7.
    Fernández A (2010) Nanoscale thermodynamics of biological interfacial tension. Pro Roy Soc A 467:559–568CrossRefGoogle Scholar
  8. 8.
    Parai MK, Huggins DJ, Cao H, Nalam MN, Ali A, Schiffer CA, Tidor B, Rana TM (2012) Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance. J Med Chem 55:6328–6341CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    The Uniprot Consortium (2014) Activities at the universal protein resource (UniProt) Nuc Acids Res 42:D191–D198Google Scholar
  10. 10.
    Hardie DG (ed) (1999) Protein phosphorylation: a practical approach. Oxford University Press, Oxford, New YorkGoogle Scholar
  11. 11.
    Zanzoni A, Carbajo D, Diella F, Gherardini PF, Tramontano A, Helmer-Citterich M, Via A (2011) Phospho3D 2.0: an enhanced database of three-dimensional structures of phosphorylation sites. Nuc Acids Res 39:D268–D271CrossRefGoogle Scholar
  12. 12.
    Liebschner D, Dauter M, Brzuszkiewicz A, Dauter Z (2013) On the reproducibility of protein crystal structures: five atomic resolution structures of trypsin. Acta Crystall Sect D 69:1447–1462CrossRefGoogle Scholar
  13. 13.
    Pietrosemoli N, Crespo A, Fernández A (2007) Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res 6:3519–3526CrossRefPubMedGoogle Scholar
  14. 14.
    Dodson G, Wlodawer A (1998) Catalytic triads and their relatives. Trends Biochem Sci 23:347–352CrossRefPubMedGoogle Scholar
  15. 15.
    Fernández A, Crespo A (2008) Protein wrapping: a molecular marker for association, aggregation and drug design. Chem Soc Rev 37:2373–2382CrossRefPubMedGoogle Scholar
  16. 16.
    Fernández A (2014) Protein structural defects are enablers and stimulators of enzyme catalysis, Scientist Ariel Fernandez Finds. Market Watch (The Wall Street Journal). Published 14 July, 2014
  17. 17.
    Fernández A, Lynch M (2011) Non-adaptive origins of interactome complexity. Nature 474:502–505CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Li H, Robertson AD, Jensen JH (2005) Very fast empirical prediction and rationalization of protein pKa values. Proteins: Struct Funct Bioinf 61:704–721Google Scholar
  19. 19.
    Jarzynski C (1997) Nonequilibrium equality for free energy differences. Phys Rev Lett 78:2690–2693CrossRefGoogle Scholar
  20. 20.
    van der Kamp MW, Mulholland AJ (2013) Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochem (ACS) 52:2708–2728CrossRefGoogle Scholar
  21. 21.
    Senn HM, Thiel W (2009) QM/MM methods for biomolecular systems. Angew Chem Int Ed 48:1198–1229CrossRefGoogle Scholar
  22. 22.
    Agarwal S, Kazi JU, Ronnstrand L (2013) Phosphorylation of the activation loop tyrosine 823 in c-Kit is crucial for cell survival and proliferation. J Biol Chem 288:22460–22468CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Sankey OF, Niklewski DJ (1989) Ab initio multicenter tight-binding model for molecular-dynamics simulations and other applications in covalent systems. Phys Rev B 40:3979–3995CrossRefGoogle Scholar
  24. 24.
    Kleinman L, Bylander DM (1982) Efficacious form for model pseudopotentials. Phys Rev Lett 48:1425–1428CrossRefGoogle Scholar
  25. 25.
    Chiodo S, Russo N, Sicilia E (2005) Newly developed basis sets for density functional calculations. J Comput Chem 26:175–184CrossRefPubMedGoogle Scholar
  26. 26.
    Fernández A (2014) Fast track communication: water promotes the sealing of nanoscale packing defects in folding proteins. J Phys Cond Matt 26:202101CrossRefGoogle Scholar
  27. 27.
    Wang J, Cieplak P, Kollman PA (2000) How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J Comput Chem 21:1049–1074CrossRefGoogle Scholar
  28. 28.
    Plesniak LA, Connelly GP, Wakarchuk WW, McIntosh LP (1996) Characterization of a buried neutral histidine residue in Bacillus circulans xylanase: NMR assignments, pH titration, and hydrogen exchange. Protein Sci 5:2319–2328CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Goedken ER, Marqusee S (2001) Co-crystal of escherichia coli RNase HI with Mn2+ ions reveals two divalent metals bound in the active site. J Biol Chem 276:7266–7271CrossRefPubMedGoogle Scholar
  30. 30.
    Kanaya S, Katayanagi K, Morikawa K, Inoue H, Ohtsuka E, Ikehara M (1991) Effect of mutagenesis at each of five histidine residues on enzymatic activity and stability of ribonuclease H from Escherichia coli. Eur J Biochem 198:437–440CrossRefPubMedGoogle Scholar
  31. 31.
    Bentley GA, Brange J, Derewenda Z, Dodson EJ, Dodson GG, Markussen J, Wilkinson AJ, Wollmer A (1992) Role of B13 Glu in insulin assembly. The hexamer structure of recombinant mutant (B13 Glu– > Gln) insulin. J Mol Biol 228:1163–1176CrossRefPubMedGoogle Scholar
  32. 32.
    Wei L, Jiang P, Yau YH, Summer H, Shocha SG, Mu Y, Pervushin K (2009) Residual structure in islet amyloid polypeptide mediates its interactions with soluble insulin. Biochemistry (ACS) 48:2368–2376CrossRefGoogle Scholar
  33. 33.
    Piao X, Bernstein A (1996) A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood 87:3117–3123PubMedGoogle Scholar
  34. 34.
    Fernandez A (2015) Packing defects functionalize soluble proteins. FEBS Lett 589:967–973Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.National Research Council–CONICETBuenos AiresArgentina
  2. 2.Former Karl F. Hasselmann Endowed Chair Professor of BioengineeringRice UniversityHoustonUSA

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