Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases

Abstract

This short article examines the usefulness of fast simulations of conformational transition paths in elucidating enzymatic mechanisms and guiding drug discovery for protein kinases. It applies the transition path method in the MOIL software package to simulate the paths of conformational transitions between six pairs of structures from the Protein Data Bank. The structures along the transition paths were found to resemble experimental structures that mimic transient structures believed to form during enzymatic catalysis or conformational transitions, or structures that have drug candidates bound. These findings suggest that such simulations could provide quick initial insights into the enzymatic mechanisms or pathways of conformational transitions of proteins kinases, or could provide structures useful for aiding structure-based drug design.

Perspectives towards antiviral drug discovery against Ebola virus

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Generating conformational transition paths with low potential-energy barriers for proteins

“…Although the shrinkage effect in the Linear and LST paths of 5'-Nucleotidase helps to avoid this problem (see Figure 8), it raises the potential-energy barrier as discussed above for Diphtheria Toxin. Note that we also applied our method on the well-known case of Tyrosin kinase [64][65][66][67] and encountered this problem from an end-loop of the structure (see Section 3 of the Supplementary Material).…”