A theoretical study on the effects of interdomain flexibility on drug encounter rate for coronavirus nucleocapsid-type proteins

To study the effects of the interdomain flexibility on the encounter rate of nucleocapsid-type protein with drug molecules, where two domains (NTD) are connected by a flexible linker and each NTD has a drug binding site, two-dimensional random walk simulation was carried out as a function of the interdomain flexibility and the drug concentration. NTDs represented as circles undergo random motions constrained by the interdomain flexibility while drug molecules are represented by lattice points. It was found that as the interdomain flexibility increases, the time interval between the drug bindings to the 1st and 2nd NTDs decreases, suggesting that the 2nd drug binding is accelerated. Furthermore, this effect was more significant at lower drug concentrations. These results suggest that the interdomain linker plays a key role in the drug binding process and thus emphasize the importance of characterization of their physicochemical properties to better evaluate the efficacy of potential drugs.