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Comparative Study
. 2003 Mar;84(3):1926-39.
doi: 10.1016/S0006-3495(03)75001-2.

Investigation of pathways for the low-pH conformational transition in influenza hemagglutinin

M Madhusoodanan  1 , Themis Lazaridis
Affiliations
Comparative Study

Investigation of pathways for the low-pH conformational transition in influenza hemagglutinin

M Madhusoodanan et al. Biophys J. 2003 Mar.

Abstract

Targeted molecular dynamics simulations were used to study the conformational transition of influenza hemagglutinin (HA) from the native conformation to putative fusogenic or postfusion conformations populated at low pH. Three pathways for this conformational change were considered. Complete dissociation of the globular domains of HA was observed in one pathway, whereas smaller rearrangements were observed in the other two. The fusion peptides became exposed and moved toward the target membrane, although occasional movement toward the viral membrane was also observed. The effective energy profiles along the paths show multiple barriers. The final low-pH structures, which are consistent with available experimental data, are comparable in effective energy to native HA. As a control, the uncleaved precursor HA0 was also forced along the same pathway. In this case both the final energy and the energy barrier were much higher than in the cleaved protein. This study suggests that 1) as proposed, the native conformation is the global minimum energy conformation for the uncleaved precursor but a metastable state for cleaved HA; 2) the spring-loaded conformational change is energetically plausible in full-length HA; and 3) complete globular domain dissociation is not necessary for extension of the coiled coil and fusion peptide exposure, but the model with complete dissociation has lower energy.

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Figures

FIGURE 1
FIGURE 1
Ribbon representation of the structure of HA along TMD Path 1 for the 1HGF → 1HTM transformation: (A) at step 0, (B) at step 3, (C) at step 6, (D) at step 9, (E) at step 12, and (F) at step 15. The segments in black are fusion peptides.
FIGURE 2
FIGURE 2
Ribbon representation of the structure of HA along TMD Path 2 for the 1HGF → 1HTM transformation: (A) at step 4, (B) at step 5, (C) at step 10, (D) at step 15, (E) at step 20, and (F) at step 25. The segments in black are fusion peptides.
FIGURE 3
FIGURE 3
Ribbon representation of the structure of HA along TMD Path 3 for the 1HGF → 1HTM transformation: (A) at step 0, (B) at step 3, (C) at step 6, (D) at step 9, (E) at step 12, and (F) at step 15. The segments in black are fusion peptides.
FIGURE 4
FIGURE 4
Ribbon representation of the structure of HA0 along TMD path for the HA0 → 1HTM transformation: (A) at step 0, (B) at step 3, (C) at step 6, (D) at step 9, (E) at step 12, and (F) at step 15. The segments in black are fusion peptides.
FIGURE 5
FIGURE 5
Top view of the ribbon diagram of the globular domains: (A) native HA, 1HGF; (B) low-pH HA of Path 1; and (C) low-pH HA of Path 3.
FIGURE 6
FIGURE 6
Energy profiles along the TMD and relaxed pathways of (A) Path 1, 1HGF → 1HTM transformation; (B) Path 2, 1HGF → 1HTM transformation; (C) Path 3, 1HGF → 1HTM transformation; and (D) HA0 → 1HTM transformation. Note the different energy scale in D.
FIGURE 7
FIGURE 7
Radius of gyration of HA along the reaction pathway of HA → 1HTM transformation.
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References

    1. Apostolakis, J., P. Ferrara, and A. Caflisch. 1999. Calculation of conformational transitions and barriers in solvated systems: application to the alanine dipeptide in water. J. Chem. Phys. 110:2099–2108.
    1. Bechor, D., and N. Ben-Tal. 2001. Implicit solvent model studies of the interactions of the influenza hemagglutinin fusion peptide with lipid bilayers. Biophys. J. 80:643–655. - PMC - PubMed
    1. Bentz, J. 1992. Intermediates and kinetics of membrane fusion. Biophys. J. 63:448–459. - PMC - PubMed
    1. Bentz, J. 2000. Membrane fusion mediated by coiled coils: a hypothesis. Biophys. J. 78:886–900. - PMC - PubMed
    1. Bentz, J., H. Ellens, and D. Alford. 1990. An architecture for the fusion site of influenza hemagglutinin. FEBS Lett. 276:1–5. - PubMed

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