Homology modeling in a dynamical world

A key concept in template-based modeling is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair Template-based modelling (TMB) results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance. This article is protected by copyright. All rights reserved.