The functional motions and related key residues behind the uncoating of coxsackievirus A16

Abstract

The coxsackievirus A16 (CVA16) is a highly contagious virus that causes the hand, foot, and mouth disease, which seriously threatens the health of children. At present, there are still no available antiviral drugs or effective treatments against the infection of CVA16, and thus it is of great significance to develop anti‐CVA16 vaccines. However, the intrinsic uncoating property of the capsid may destroy the neutralizing epitopes and influence its immunogenicity, which hinders the vaccine developments. In the present work, the functional‐quantity‐based elastic network model analysis method developed by our group was extended to combine with group theory to investigate the uncoating motions of the CVA16 capsid, and then the functionally key residues controlling the uncoating motions were identified by our functional‐quantity‐based perturbation method. Several motion modes encoded in the topological structure of the capsid were revealed to be responsible for the uncoating of CVA16 particle. These modes predominantly contribute to the fluctuation of the gyration radius of the capsid. Then, by using the perturbation method, four clusters of key sites involved in the uncoating motions were identified, whose perturbations induce significant changes in the fluctuation of the gyration radius. These key residues are mainly located at the 2‐fold channels, the quasi 3‐fold channels, the bottom of the canyons, and the inter‐subunit interfaces around the 3‐fold axes. Our studies are helpful for better understanding the uncoating mechanism of the CVA16 capsid and provide potential target sites to prevent the uncoating motions, which is valuable for the vaccine design against CVA16.

Identification of the Intrinsic Motions and Related Key Residues Responsible for the Twofold Channel Opening of Poliovirus Capsid by Using an Elastic Network Model Combined with an Internal Coordinate

“…This motion results in the collapse of the regions around the fivefold axes and expansion outward of the regions around the twofold and quasi threefold axes. A similar rotation motion has also been observed in the intrinsic motions of other virus capsids, for example, enterovirus 71­(EV71) and coxsackievirus A16­(CVA16) . The third motion mode that mostly contributes to the opening of the twofold channels is shown in Figure c.…”

“…Fox et al also shows that some mutations that stabilize the PV capsid in the unexpansive conformation existed in the canyon region . The study of He et al also revealed that several sites in the canyon region significantly regulated the uncoating of coxsackievirus A16 capsid . Reisdorph et al found that the mobility of the canyon region is critical for the capsid uncoating of rhinovirus, which is structurally similar to PV, and the binding of antiviral drugs or residue mutations in this region can block the functional motions of the virus …”

“…40 The study of He et al also revealed that several sites in the canyon region significantly regulated the uncoating of coxsackievirus A16 capsid. 34 Reisdorph et al found that the mobility of the canyon region is critical for the capsid uncoating of rhinovirus, which is structurally similar to PV, and the binding of antiviral drugs or residue mutations in this region can block the functional motions of the virus. 41 The key sites of group 3 are located at the region across the quasi threefold channel of the PV capsid, including the residues Val291, Ile335, and Leu340 from VP0, Val215 and Leu228 from VP1, and Asp140, Ser183 from VP3.…”

“…A similar rotation motion has also been observed in the intrinsic motions of other virus capsids, for example, enterovirus 71(EV71) 33 and coxsackievirus A16(CVA16). 34 The third motion mode that mostly contributes to the opening of the twofold channels is shown in Figure 3c. In this motion, each protomer as a whole undergoes a rotation motion approximately along the tangential direction of the capsid surface, and this motion leads to the obvious opening of the twofold channels.…”