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. 2015 Feb 17;112(7):2034-9.
doi: 10.1073/pnas.1414190112. Epub 2015 Feb 2.

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Xiancheng Zeng  1 , Suchetana Mukhopadhyay  2 , Charles L Brooks 3rd  3
Affiliations

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Xiancheng Zeng et al. Proc Natl Acad Sci U S A. .

Abstract

Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.

Keywords: alphavirus; constant pH molecular dynamics; envelope protein; membrane fusion; pH.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Structure and organization of alphaviral envelope proteins. (A) The alphaviral envelope modeled in our simulations. (B) The alphaviral envelope proteins in an MAU. (C) The heterodimer of E2 (DA–DB–DC) and E1 (DI–DII–DIII). (D) Structures of a viral spike in different conformational states simulated for shifts in pKa values and thermodynamic stabilities. E1 proteins are shown in blue, cyan, and light blue. E2 proteins are shown in red, magenta, and pink.
Fig. 2.
Fig. 2.
ΔpKa values and the corresponding shifts in thermodynamic stability (ΔΔG) at residue-level resolution for (A) the M→FI activation step and (B) the E2 dissociation (FI→Dis) and HT formation (FI→HT) steps. ΔpKaA→B values of individual residues are represented by vertical bars for Asp (red), Glu (green), and His (blue) residues in E1 (solid bars) and E2 (outlined bars) proteins, with scales on the left y axes. Integration of −ΔΔGM→FI, −ΔΔGFI→HT, and −ΔΔGFI→Dis per monomer (with pH 5.5 and pHref 7.5) is shown in black lines, with scales on the right y axes.
Fig. 3.
Fig. 3.
pH dependence of the shifts of thermodynamic stabilities per viral spike, ΔΔG(pH), for the M→FI, FI→Dis (E2), and FI→HT (E1) processes. ΔΔG at the reference pH, pHref 7.5, is set to 0 kcal/mol, indicated by +.
Fig. 4.
Fig. 4.
Correlation of sequence conservation and pH sensitivity. Sequence conservation frequencies of all His residues on E2 and E1 of CHIKV with the corresponding ΔΔG contributions to the M→FI and FI→HT steps are shown by red + and blue ×, respectively. A conservation frequency of 13 represents a strictly conserved sequence among the 13 alphaviral species surveyed here.
Fig. 5.
Fig. 5.
Locations of pH-sensitive residues on (A) the (E2–E1)3 viral spike complex in the M state and (B) the (E1)3 in the HT state. Strictly conserved pH-sensitive residues that contribute to the M→FI and FI→HT steps are mapped in green and orange beads, respectively, on the alphaviral spike. Two nonstrictly conserved residues with ΔΔG > 1 kcal/mol in the M→FI and FI→HT steps are shown in smaller beads. In B, one of the E1 monomers (cyan) is displaced and rotated to show the residues on the trimeric interface inside the HT.
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