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Nonpolar interactions of thrombin and its inhibitors at the fibrinogen recognition exosite: thermodynamic analysis.
Biochemistry. 1996 Oct 08; 35(40):13021-9.B

Abstract

Nonpolar interactions play a major role in the association of the fibrinogen recognition exosite of thrombin with the C-terminal fragment (55-65), Asp-Phe-Glu-IIe-Pro-Glu-Glu-Tyr-Leu-Gln, of hirudin, which is a naturally occurring thrombin inhibitor. The thermodynamic details (free energy, enthalpy, entropy, and heat capacity) of the molecular recognition are studied by using five analogs of a synthetic bivalent thrombin inhibitor (P552), tert-butylbenzensulfonyl-Arg-(D-pipecolic acid)-(12-amino-dodecanoic acid)-(gamma-aminobutyric acid)-hirudin55-65. The residue of PheH56, IleH59, ProH60, TyrH63, or LeuH64 in hirudin 55-65 segment is substituted by Gly in each analog in order to elucidate the contributions of these nonpolar side chains. The results show that the interactions of these nonpolar side chains with thrombin are enthalpy-driven, except for the contribution of the PheH56 side chain which is entropy-driven. Interestingly, molecular modeling predicts a large conformational change due to the Gly substitution of PheH56. In analyzing the correlation among the thermodynamic and structural properties of the nonpolar interaction, a good correlation is observed between the binding free energy and the hydrophobicity of the molecular surface; i.e., tighter binding is observed as more nonpolar atoms are buried and more polar atoms are exposed upon molecular association.

Authors+Show Affiliations

National Research Council of Canada, Biotechnology Research Institute, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8855937

Citation

Cheng, Y, et al. "Nonpolar Interactions of Thrombin and Its Inhibitors at the Fibrinogen Recognition Exosite: Thermodynamic Analysis." Biochemistry, vol. 35, no. 40, 1996, pp. 13021-9.
Cheng Y, Slon-Usakiewicz JJ, Wang J, et al. Nonpolar interactions of thrombin and its inhibitors at the fibrinogen recognition exosite: thermodynamic analysis. Biochemistry. 1996;35(40):13021-9.
Cheng, Y., Slon-Usakiewicz, J. J., Wang, J., Purisima, E. O., & Konishi, Y. (1996). Nonpolar interactions of thrombin and its inhibitors at the fibrinogen recognition exosite: thermodynamic analysis. Biochemistry, 35(40), 13021-9.
Cheng Y, et al. Nonpolar Interactions of Thrombin and Its Inhibitors at the Fibrinogen Recognition Exosite: Thermodynamic Analysis. Biochemistry. 1996 Oct 8;35(40):13021-9. PubMed PMID: 8855937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nonpolar interactions of thrombin and its inhibitors at the fibrinogen recognition exosite: thermodynamic analysis. AU - Cheng,Y, AU - Slon-Usakiewicz,J J, AU - Wang,J, AU - Purisima,E O, AU - Konishi,Y, PY - 1996/10/8/pubmed PY - 1996/10/8/medline PY - 1996/10/8/entrez SP - 13021 EP - 9 JF - Biochemistry JO - Biochemistry VL - 35 IS - 40 N2 - Nonpolar interactions play a major role in the association of the fibrinogen recognition exosite of thrombin with the C-terminal fragment (55-65), Asp-Phe-Glu-IIe-Pro-Glu-Glu-Tyr-Leu-Gln, of hirudin, which is a naturally occurring thrombin inhibitor. The thermodynamic details (free energy, enthalpy, entropy, and heat capacity) of the molecular recognition are studied by using five analogs of a synthetic bivalent thrombin inhibitor (P552), tert-butylbenzensulfonyl-Arg-(D-pipecolic acid)-(12-amino-dodecanoic acid)-(gamma-aminobutyric acid)-hirudin55-65. The residue of PheH56, IleH59, ProH60, TyrH63, or LeuH64 in hirudin 55-65 segment is substituted by Gly in each analog in order to elucidate the contributions of these nonpolar side chains. The results show that the interactions of these nonpolar side chains with thrombin are enthalpy-driven, except for the contribution of the PheH56 side chain which is entropy-driven. Interestingly, molecular modeling predicts a large conformational change due to the Gly substitution of PheH56. In analyzing the correlation among the thermodynamic and structural properties of the nonpolar interaction, a good correlation is observed between the binding free energy and the hydrophobicity of the molecular surface; i.e., tighter binding is observed as more nonpolar atoms are buried and more polar atoms are exposed upon molecular association. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/8855937/Nonpolar_interactions_of_thrombin_and_its_inhibitors_at_the_fibrinogen_recognition_exosite:_thermodynamic_analysis_ L2 - https://doi.org/10.1021/bi961039c DB - PRIME DP - Unbound Medicine ER -