Homology Modeling In A Dynamical World

Abstract

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.\n\nIn 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.\n\nAuthor summaryTemplate-based modelling (TBM) is the most reliable and fastest approach to obtain protein structural models. TBM relies in the high correlation between sequence and structural divergence, with the practical consequence that proteins that are similar at the sequence level will also be similar at the structural level, allowing in this way the selection of the better template to obtain the 3D model of the target sequence. However, protein native state could be described by a collection of conformers in equilibrium where their structural differences are called conformational diversity.\n\nIn this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We firstly found that the extent of conformational diversity can be as high as the maximum structural differences reached by families differing in their sequences. In these proteins with higher conformational diversity levels, the well-established correlation between sequence and structural divergence is nosier than previously suggested due to the presence of structural change without sequence variation. This lack of correlation could impair TBM results due to the uncertainty in the correct template selection. Finally, we also found that the presence of order/disorder can provide useful beforehand information for better TBM performance.