Biomimetic Design Of Peptide Neutralizer Of Ebola Virus

Ebola virus(EBOV)belongs to the Filoviridae family,which can cause severe hemorrhagic fever in humans and non-primates.With a high mortality rate up to 90%,it becomes a research hot-pot in the world.EBOV is a potential public health threat,and is classified as a Biosafety Level 4 and Class A pathogen,making it a focus of biological defense research.At present,the research on the prevent and cure of EBOV includes antibody-based,vaccine-based,and drug-based strategies However,none of them has been approved by FDA.Therefore,it is of significant importance to research and develope neutralizing agents for EBOV.In the present study,molecular dynamics(MD)simulation and molecular mechanics-Poisson-Boltzmann surface area(MM-PBSA)method were used to analyze the molecular interactions between EBOV glycoprotein GPcl and an antibody ADI-15946 that was obtained from human,followed by the design of neutralizer.The results showed that hydrophobic interaction was the main driving force for the formation of the complex,while electrostatic interaction was unfavorable for the binding.The residues with the most favorable contributions to binding were identified through free energy decomposition,including Y107,F108,D109,W110 of ADI-15946,and R559,K510,P513,C511 of GPcl.Among these key residues,F108,W110 of ADI-15946 and P513 of GPcl were hydrophobic residues,which were essential for the stability of the complex.Based on this,an affinity binding model(ABM)for the interaction between ADI-15946 and GPcl was constructed and used for the biomimetic design of neutralizers.According to the spatial distribution of Y107,F108,D109,W110 and R113 in ABM,the neutralizer sequence was designed as YFDWXXR,leading to 400 candidates.Then the affinity of each candidate to GPcl was evaluated by molecular docking,structural similarity,and MD simulation.Finally,two candidates,YFDWHMR and YFDWRYR,were obtained,which showed strong binding on GPcl.Therefore,the molecular interactions between antibody ADI-15946 and GPcl was studied and used for the biomimetic design of neutralizing agents.Two neutralizers,YFDWHMR and YFDWRYR were obtained,which would be helpful for the research and design of new drugs for EBOV.