Plasticity of the 340-Loop in Influenza Neuraminidase Offers New Insight for Antiviral Drug Development.

Nanyu Han,Justin Ng,Yanpeng Li,Zunxi Huang,Yuguang Mu

doi:10.3390/ijms21165655

Abstract

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342–347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 μs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.

Highlights

Since the beginning of the last century, multiple pandemics caused by influenza viruses have severely impacted public health [1]
Our study reveals that seven of the nine NA subtypes exhibit an open 340-cavity, the calcium ion plays an important role in maintaining the conformation of the 340-loop, and the 340-loop is a canonical approach site in the sialic acid (SA) binding mechanism
Our results indicate that the 340-loop is a critical motif in NA, and the 340-cavity is a valuable hotspot for anti-influenza drug design

Summary

Introduction

Since the beginning of the last century, multiple pandemics caused by influenza viruses have severely impacted public health [1]. Exploring the structural features of NAs and identifying the SA binding path are of great importance in designing anti-influenza drugs [7,8]. The crystal structures of group-1 NAs contain a unique characteristic, the 150-cavity, which can be exploited to develop new anti-influenza drugs [10]. Questions regarding whether the 340-cavity is prevalent in NAs, whether the 340-loop participates in the substrate binding process, and the structural dynamics of the 340-loop in other NA subtypes have never been explored. Our study reveals that seven of the nine NA subtypes exhibit an open 340-cavity, the calcium ion plays an important role in maintaining the conformation of the 340-loop, and the 340-loop is a canonical approach site in the SA binding mechanism. Our results indicate that the 340-loop is a critical motif in NA, and the 340-cavity is a valuable hotspot for anti-influenza drug design

Results

The 340-Loop Is Involved in the SA Binding Pathway

A Calcium Ion Controls the Stability of the 340-Loop

Discussion

MD Simulation Details

Sliding Binding-Box Docking