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Does conformational free energy distinguish loop conformations in proteins?

J L Pellequer1, S W Chen

  • 1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. pelleque@scripps.edu

Biophysical Journal
|November 25, 1997
PubMed
Summary

This study introduces a computational method to screen protein loop conformations for homology modeling. It identifies stable loop structures by calculating conformational free energies, finding that gas phase energy is key for accurate antibody CDR modeling.

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Area of Science:

  • Computational Biology
  • Structural Biology
  • Protein Modeling

Background:

  • Protein homology modeling is crucial for structure prediction but faces limitations in accurately modeling loops.
  • Loop regions are critical for protein function and stability, yet their conformational flexibility poses modeling challenges.

Purpose of the Study:

  • To develop and apply a computational method for screening and selecting optimal loop conformations in protein models.
  • To evaluate the stability of loop conformations using free energy calculations in solution.

Main Methods:

  • A computational scheme was developed to calculate conformational free energies of loops using a thermodynamic cycle.
  • Gas phase free energy was determined using CHARMm potential energy.
  • Solvation free energy was computed using finite-difference Poisson-Boltzmann and surface area-based methods.

Related Experiment Videos

  • A database of antibody hypervariable loops (complementarity-determining regions, CDRs) was generated from crystal structures and inserted into an antibody framework.

    • Main Results:

    • The computational scheme successfully identified loop conformations with reference-like CDR geometry based on gas phase free energy.
    • Solvation energy calculations showed a complex role, sometimes hindering discrimination of reference-like CDRs, especially for shorter loops.
    • Most reference-like loop conformations were clearly separated by a gap in gas phase free energy.
    • Naturally occurring antibody loops were found to be optimal models for longer CDRs (≥ 6 residues) due to better backbone atom packing.

    Conclusions:

    • Gas phase conformational free energy is a significant factor in selecting accurate loop conformations for antibody CDRs.
    • Solvation effects introduce complexity and can sometimes misrepresent the stability of loop conformations.
    • The study provides a robust computational approach for improving protein loop modeling, particularly for antibody CDRs.