Length of Mucin-Like Domains Enhance Cell-Ebola Virus Adhesion by Increasing Binding Probability

Abstract

The Ebola virus (EBOV) hijacks normal physiological processes by apoptotic mimicry in order to be taken up by the cell it infects. The initial adhesion of the virus to the cell is based on the interaction between T-cell immunoglobulin and mucin domain protein, TIM, on the cell-surface and phosphatidylserine (PS) on the viral outer surface. Therefore, it is important to understand the interaction between EBOV/PS and TIM, with selective blocking of the interaction as a potential therapy. Recent experimental studies have shown that for TIM-dependent EBOV entry, a Mucin-like Domain (MLD) with a length of at least 120 amino acids is required, possibly due to the increase of area of the PS-coated surface sampled. We examine this hypothesis by modeling the process of TIM-PS adhesion using a coarse-grained molecular model. We find that the strength of bound PS−TIM pairs is essentially independent of TIM length. TIMs with longer MLDs have higher average binding strengths because of an increase in the probability of binding between EBOV and TIM proteins. Similarly, we find that for larger persistence length (less flexible) the average binding force decreases, again because of a reduction in the probability of binding.Statement of Significance This work studies the mechanism of TIM-dependent adhesion of the Ebola virus to a cell. Through coarse grained modeling we show that longer TIM stalks adhere more easily as they can sample a larger area, thus offering a mechanistic interpretation of an experimental finding. Better mechanistic understanding can lead to therapeutic ideas for blocking adhesion.View Full Text