Improvement of comparative modeling by the application of conserved motifs amongst distantly related proteins as additional restraints

Abstract

Protein comparative modeling has useful applications in large-scale structural initiatives and in rational design of drug targets in medicinal chemistry. The reliability of a homology model is dependent on the sequence identity between the query and the structural homologue used as a template for modeling. Here, we present a method for the utilization and conservation of important structural features of template structures by providing additional spatial restraints in comparative modeling programs like MODELLER. We show that root mean square deviation at C^α positions between the model and the corresponding experimental structure and the quality of the models can be significantly improved for distantly related systems by utilizing additional spatial restraints of the template structures. We demonstrate the influence of such approaches to homology modeling during distant relationships in understanding functional properties of protein such as ligand binding using cytochrome P450 as an example.

Figure Example of a modeling triad. Structures of flavodoxin from Clostridium beijerinckii (PDB code, 5nul) and flavodoxin from Chondrus crispus (PDB code, 2fcr) that are equidistant in sequence identity (Seq. ID.) and structural similarity (RMSD¹) to the third flavodoxin member (from Desulfovibrio vulgaris, PDB code, 1akr)