Human parainfluenza virus type 3 is a clinically-significant pathogen and is the causative agent of pneumonia and bronchiolitis in children. In this study the solution dynamics of human parainfluenza type 3 haemagglutinin-neuraminidase (HN) have been investigated. A flexible loop around Asp216 that adopts an open conformation in direct vicinity of the active site of the apo-form of the protein has been identified. Furthermore this loop closes upon inhibitor binding. These findings have implications in anti-parainfluenza virus drug discovery.

A Molecular Dynamics (MD) simulation approach has been used to identify a flexible region of hPIV-3 HN protein that lies in immediate vicinity to the N-acetylneuraminic acid binding site. hPIV-3 HN is an essential protein in the lifecycle of the virus and is used by the virus in both attachment and release from host cells. Our study represents the first MD investigation on a validated drug discovery target for anti-parainfluenza virus therapeutics development. The loop comprising the residues 210-221, the so-called 216-loop, populates different conformations in the apo-form of the HN in comparison to the inhibitor-bound protein. 

The present MD study leads us to propose that this loop flexibility may be a common feature of all viral sialidases and may be an important determinant of glycan receptor specificity. The observations made better inform the structure-based inhibitor design process and suggest that bulkier substituents can be accommodated at C4 position of the Neu5Ac2en template. Present findings provide new opportunities towards the discovery of novel therapeutics to treat parainfluenza viral infections.