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BioMed Research International
Volume 2014 (2014), Article ID 572409, 10 pages
Research Article

Local Packing Density Is the Main Structural Determinant of the Rate of Protein Sequence Evolution at Site Level

1Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30050, Taiwan
2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu 30050, Taiwan
3Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, Martín de Irigoyen 3100, San Martín, 1650 Buenos Aires, Argentina

Received 28 February 2014; Revised 6 June 2014; Accepted 9 June 2014; Published 9 July 2014

Academic Editor: Liam McGuffin

Copyright © 2014 So-Wei Yeh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Functional and biophysical constraints result in site-dependent patterns of protein sequence variability. It is commonly assumed that the key structural determinant of site-specific rates of evolution is the Relative Solvent Accessibility (RSA). However, a recent study found that amino acid substitution rates correlate better with two Local Packing Density (LPD) measures, the Weighted Contact Number (WCN) and the Contact Number (CN), than with RSA. This work aims at a more thorough assessment. To this end, in addition to substitution rates, we considered four other sequence variability scores, four measures of solvent accessibility (SA), and other CN measures. We compared all properties for each protein of a structurally and functionally diverse representative dataset of monomeric enzymes. We show that the best sequence variability measures take into account phylogenetic tree topology. More importantly, we show that both LPD measures (WCN and CN) correlate better than all of the SA measures, regardless of the sequence variability score used. Moreover, the independent contribution of the best LPD measure is approximately four times larger than that of the best SA measure. This study strongly supports the conclusion that a site’s packing density rather than its solvent accessibility is the main structural determinant of its rate of evolution.