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Electrostatic interactions in hirudin-thrombin binding

K A Sharp1

  • 1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia 19104-6059, USA. sharp@crystal.med.upenn.edu

Biophysical Chemistry
|August 30, 1996
PubMed
Summary
This summary is machine-generated.

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Mutating hirudin's acidic residues (aspartate and glutamate) to asparagine or glutamine reduced anticoagulant activity by altering electrostatic interactions with thrombin. Structural changes can compensate for unfavorable interactions in multiple mutants.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Hirudin is a potent anticoagulant that inhibits thrombin.
  • Its binding affinity is mediated by acidic residues forming salt bridges.
  • Previous studies mutated these residues to asparagine or glutamine.

Purpose of the Study:

  • To computationally analyze the electrostatic contributions to hirudin-thrombin binding energy changes after mutations.
  • To investigate the impact of charge-charge interactions, solvation, pKa shifts, and ionic strength on binding.

Main Methods:

  • Finite-difference Poisson-Boltzmann calculations were employed.
  • Analysis included charge-charge interactions, solvation, residual interactions, pKa shifts, and ionic strength.
  • Comparison with experimental data for single and multiple mutants.

Related Experiment Videos

Main Results:

  • Calculated single mutant binding energies generally agreed with experimental values, with an exception for D55N.
  • Multiple mutation effects were often overestimated by calculations.
  • pKa shifts significantly impacted binding for E58, possibly due to crystal contacts.
  • Unfavorable electrostatic interactions between acidic residues were observed, but experimental data suggested compensatory structural changes in multiple mutants.

Conclusions:

  • Mutations lead to a loss of favorable charge-charge interactions, reducing complex stability.
  • This loss is largely offset by reduced desolvation penalties and residual polar interactions in Asn/Gln mutants.
  • Structural rearrangements can mitigate unfavorable electrostatic interactions when multiple acidic residues are mutated.