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Stability of macromolecular complexes.

Natasja Brooijmans1, Kim A Sharp, Irwin D Kuntz

  • 1Graduate Program in Chemistry and Chemical Biology, University of California-San Francisco, San Francisco, California 94143-0446, USA.

Proteins
|September 5, 2002
PubMed
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The strength of macromolecular interactions does not increase with interface size as expected. Instead, binding affinity plateaus, suggesting functional constraints, not physical limits, influence complex stability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Macromolecular interactions are vital for biological processes.
  • General principles for predicting interaction strength are limited.
  • Previous work suggested additivity of binding energy with interface size.

Purpose of the Study:

  • To investigate the relationship between interface size and binding affinity in macromolecular complexes.
  • To determine if binding free energy increases monotonically with interface size.
  • To explore the implications for molecular design and protein stability.

Main Methods:

  • Analysis of binding free energies for high-affinity macromolecular complexes.
  • Comparison with existing data on protein-ligand interactions.

Related Experiment Videos

  • Evaluation of the role of interface size on binding affinity.

    • Main Results:

    • Highest-affinity complexes show constant binding free energy, irrespective of interface size (except DNA duplexes).
    • Maximum affinity is approximately 1.5 kcal/mol per non-hydrogen atom or 120 cal/mol Ų of buried surface area.
    • Lack of affinity increase with size is attributed to functional/evolutionary constraints, not physical limitations.

    Conclusions:

    • Macromolecular complex stability is not maximized due to functional and evolutionary pressures.
    • This suggests opportunities for increasing complex stability through molecular design.
    • Small molecule inhibitors of macromolecular interactions are feasible.
    • Different protein-protein complex classes show varying maximal stability.