Paula Petrone and Vijay S. Pande.
Biophysical Journal (2006)
SUMMARY: In allosteric regulation, protein activity is altered when ligand binding (or unbinding) causes changes in the protein conformation. Little is known about which aspects of the protein architecture are responsible for allosteric regulation, however most of these changes involve collective displacements of atoms (domain and hinge-bending motions) which are likely to occur in the microsecond timescale. Normal mode analysis (NMA) decouples the complex motions and fluctuations of proteins into a linear combination of orthogonal basis vectors, each representing an independent concerted harmonic motion with a characteristic frequency. In principle, it would be a natural basis in which to represent conformational change that involves collective motions of atoms. This paper addresses the limitations of NMA, namely how many normal modes are necessary to achieve a certain degree of accuracy in the representation.
TECHNICAL ABSTRACT: We suggest a simple method to assess how many normal modes are needed to map a conformational change. By projecting the conformational change onto a subspace of the normal mode vectors and, using RMSD as a test of accuracy, we find that the first 20 modes only contribute 50% or less of the total conformational change in four test cases (myosin, calmodulin, NtrC, and hemoglobin). In some allosteric systems, like the molecular switch NtrC, the conformational change is localized to a limited number of residues. We find that many more modes are necessary to accurately map this collective displacement. In addition, the normal mode spectra can provide useful information about the details of the conformational change, especially when comparing structures with different bound ligands, in this case, calmodulin. Indeed, this approach presents normal mode analysis as a useful basis in which to capture the mechanism of conformational change, and shows that the number of normal modes needed to capture the essential collective motions of atoms should be chosen according to the required accuracy.