Dynamics of Zika Virus Capsid Protein in Solution: The Properties and Exposure of the Hydrophobic Cleft Are Controlled by the α-Helix 1 Sequence

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Abstract
Zika virus (ZIKV) became an important public health concern since the infection has been correlated to the development of microcephaly and other neurological disorders. Although the structure of virion has been determined by cryo-EM, information on the nucleocapsid is lacking. We used NMR to determine the solution structure and dynamics of full length ZIKV capsid protein (ZIKVC). Although most of the protein is structured as described for dengue and West Nile viruses’ capsid proteins, as well as for the truncated ZIKVC (residues 23-98), here we show important differences in the α-helix 1 and N-terminal intrinsically disordered region (IDR). We distinguished two dynamical regions in ZIKVC IDR: a highly flexible N-terminal end and a transitional disordered region, indicating that it contains ordered segments rather than being completely flexible. The unique size, orientation of α-helix 1 partially occludes protein hydrophobic cleft. Measurements of the dynamics of α-helix 1, surface exposure and thermal susceptibility of each backbone amide 1H in protein structure revealed the occlusion of the hydrophobic cleft by α1/α1´ and supported a α-helix 1 position uncertainty. Based on the findings described here, we propose that the dynamics of ZIKVC structural elements responds for a structure-driven regulation of protein interaction with intracellular hydrophobic interfaces, which would impact in the switches necessary for nucleocapsid assembly. Subtle differences in the sequence of α-helix 1 impact on its size and orientation and on the degree of exposure of the hydrophobic cleft, suggesting that α-helix 1 is a hotspot for evolutionary adaptation of flaviviruses’ capsid proteins.
Funding Information
  • Minist??rio da Ci??ncia, Tecnologia e Inova????o (306669/2013-7, 457773/2014-6, 309564/2017-4)
  • Minist??rio da Ci??ncia, Tecnologia e Inova????o (0267/16)
  • Funda????o Carlos Chagas Filho de Amparo ?? Pesquisa do Estado do Rio de Janeiro (201316, 201167, 204432, 215141, 210361, 239229)

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