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An Analysis of Core Deformations in Protein Superfamilies

Alejandra Leo-Macias ^*, Pedro Lopez-Romero ^*, Dmitry Lupyan , Daniel Zerbino ^* and Angel R. Ortiz ^*

^* Bioinformatics Unit, Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Cantoblanco, Madrid, Spain; and Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York

Correspondence: Address reprint requests to Angel R. Ortiz, Tel.: 34-91-497-2376; Fax: 34-91-497-4799; E-mail: aro{at}cbm.uam.es.

An analysis is presented on how structural cores modify their shape across homologous proteins, and whether or not a relationship exists between these structural changes and the vibrational normal modes that proteins experience as a result of the topological constraints imposed by the fold. A set of 35 representative, well-populated protein families is studied. The evolutionary directions of deformation are obtained by using multiple structural alignments to superimpose the structures and extract a conserved core, together with principal components analysis to extract the main deformation modes from the three-dimensional superimposition. In parallel, a low-resolution normal mode analysis technique is employed to study the properties of the mechanical core plasticity of these same families. We show that the evolutionary deformations span a low dimensional space of 4–5 dimensions on average. A statistically significant correspondence exists between these principal deformations and the 20 slowest vibrational modes accessible to a particular topology. We conclude that, to a significant extent, the structural response of a protein topology to sequence changes takes place by means of collective deformations along combinations of a small number of low-frequency modes. The findings have implications in structure prediction by homology modeling.

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