Protein modeling is becoming an increasingly critical tool to fully understand chemical systems. Even when there is no crystal structure for a target of interest, modeling methods can accurately propose likely protein structures and binding mechanisms. Homology Modeling allows creation of reliable 3D structures of your protein targets of interest when no experimental structure is available. Protein homology models are valuable for finding potential pockets, grooves and binding sites for drug design, nucleic acid binding and protein-protein interactions. A protein homology model helps predict the bioactive conformation of a ligand, facilitating efficient ligand design. Creating a homology model requires a correct primary sequence and a 3D template protein structure(s) with high resolution and structurally complete, particularly in the active site or specific region of interest. An accurate homology requires that the template share a significant sequence homology with the protein of interest (usually a minimum of 35% sequence homology). Once aligned, the differing amino acids in the template are replaced with the equivalent amino acids in the protein of interest (Figure 1). The ever-growing number of available protein structures make homology modeling a more feasible computational technique for protein structure prediction. The overall quality of a homology model can be assessed by Ramachandran plots that can verify if the residue dihedral angles fall within permitted space (Figure 2) and protein contact map plots. The use of an ensemble of protein structures for modeling, checking structural differences, and perform a multiple sequence alignment might improve the quality of the model. Placing structural or catalytic waters within the structure, alternate loop conformations with FREAD algorithm and performing molecular dynamics simulations and ensuring the model represented the lowest energy structure can also improve the quality of the model. Cresset Discovery Solutions has extensive experience in homology modeling and can support/work alongside you on your project. In past projects, we showed how Cresset’s XED force field applied to homology modeling can be highly effective in predicting the binding site of an anti-malarial inhibitor1 and a flavors binding mechanism for a GPCR with unresolved structure. That lead to insights and breakthroughs and made it possible to move projects on to the next downstream workflow.
Figure 1. A known 4-Hydroxyphenylpyruvate dioxygenase (HPPD) X-ray structure (PDBID: 7CQS) (Left) used as template to create a homology model of the HPPD from Ambrosia artemisiifolia in a homology modellng experiment (Right).
Figure 2. Ramachandran plot for a modeled protein illustrates whether the residue backbone dihedral angles, phi φ and psi Ψ, fall within permitted regions for ß-sheet, right-handed α-helix and left-handed α-helix.