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.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. Author 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.In 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 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/135004 doi: bioRxiv preprint first posted online May. 6, 2017; 3 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 ...

Ensembles from Ordered and Disordered Proteins Reveal Similar Structural Constraints during Evolution

“…This effect operates over SCPE substitution matrices, which are site and conformer specific but are evaluated using sequence alignments from corresponding homologous families. Thus, evolutionary information contained in those alignments reflects constraints of several sorts, such as structural divergence [41] or dynamical adaptations [56,57]…”

What the protein data bank tells us about the evolutionary conservation of protein conformational diversity

“…Therefore, in this manuscript, we evaluate the conservation of large-scale conformational changes directly using experimentally solved structures deposited in the Protein Data Bank (PDB). 25 The PDB contains, on average, more than six coordinate sets per individual protein that provide a sample of the protein's conformational ensemble, [26][27][28] often capturing distinct conformational and functional states of the protein and thus characterizing different "neighborhoods" in the ensemble. A previous study used this multiplicity of coordinate sets to show that protein pairs that share one similar conformation often share multiple conformations-suggesting that their conformational spaces are conserved.…”