Investigation of Pathways for the Low-pH Conformational Transition in Influenza Hemagglutinin

Madhusoodanan, M.; Lazaridis, Themis

doi:10.1016/s0006-3495(03)75001-2

Cited by 16 publications

(18 citation statements)

References 62 publications

(84 reference statements)

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“…However, experimental studies on HA2 coiled‐coil‐like synthetic peptides15 and HA217, 18 have shown that the coiled‐coil structure is stable at neutral pH and low pH, implying that there is no direct relationship between low pH and the loop‐to‐helix transition. In agreement with the experimental observations, a computational study has shown that the low pH conformation of the coiled‐coil part of HA by itself is energetically more stable than the native conformation 19. All these results imply that the HA2 coiled‐coil might form by a mechanism that is essentially independent of low pH.…”

Section: Introductionsupporting

confidence: 81%

“…Again, the negative difference of the free energy (−37.6 kcal·mol −1 ) implies that the loop‐to‐helix transition can take place spontaneously at any pH in the range of 4–10, since the L150 conformer is metastable (see also Possible Role of Low pH for the Conformational Changes of HA section). A computational study based on two different energy functions, the effective energy function EEF1 defined by the authors and generalized Born model, has already shown that the effective energy of the HA2 coiled‐coil conformation is lower than that of the loop conformation for the residues present in 1HTM, also indicating that in the absence of HA1 HA2 folds into the 1HTM conformation 19. Since at any pH in the range of 4–10 the electrostatic interaction between the protein and the solvent dominates the free energy difference between L150 and H150 (−452.7 ± 44.6 kcal·mol −1 in Table II), the protein–water interactions are the major driving force of the loop‐to‐helix transition.…”

Section: Resultsmentioning

confidence: 99%

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Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

et al. 2008

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Fusion of influenza virus with the endosomal membrane of the host cell is mediated by the homotrimer-organized glycoprotein hemagglutinin (HA). Its fusion activity is triggered by a low pH-mediated conformational change affecting the structure of the HA1 and HA2 subunits. The HA2 subunits undergo a loop-to-helix transition leading to a coiled-coil structure, a highly conserved motif for many fusion mediating viral proteins. However, experimental studies showed that the HA2 coiled-coil structure is stable at neutral and low pH, implying that there is no direct relationship between low pH and the HA2 loop-to-helix transition. To interpret this observation, we used a computational approach based on the dielectric continuum solvent model to explore the influence of water and pH on the free energy change of the transition. The computations showed that the electrostatic interaction between HA2 fragments and water is the major driving force of the HA2 loop-to-helix transition leading to the coiled-coil structure, as long as the HA1 globular domain covering the HA2 subunits in the nonfusion competent conformation is reorganized and thereby allows water molecules to interact with the whole loop segments of the HA2 subunits. Moreover, we show that the energy released by the loop-to-helix transition may account for those energies required for driving the subsequent steps of membrane fusion. Such a water-driven process may resemble a general mechanism for the formation of the highly conserved coiled-coil motif of enveloped viruses.

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Section: Introductionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

et al. 2008

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“…Detailed validation and prediction aimed at understanding the preferential oligomerization state of different coiled-coils88,113,125.…”

Section: Introductionmentioning

confidence: 99%

“…The use of targeted or force-induced MD simulations to investigate alterations in coiled-coil structure and dynamics, including calculation of a conformational exchange pathway connecting two different crystal structures of the anti-parallel coiled-coil of seryl tRNA synthetase132, transitions from the native to the putative fusogenic conformations of influenza hemagglutinin at low pH88, transitions among different GCN4 structures92, and investigation of putative conformational transitions in engineered prion peptides89.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics guided study of salt bridge length dependence in both fluorinated and non‐fluorinated parallel dimeric coiled‐coils

Pendley

Cheatham

2008

Proteins

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The α-helical coiled-coil is one of the most common oligomerization motifs found in both native and engineered proteins. To better understand the stability and dynamics of coiled-coil motifs, including those modified by fluorination, several fluorinated and non-fluorinated parallel dimeric coiled-coil protein structures were designed and modeled. We also attempt to investigate how changing the length and geometry of the important stabilizing salt bridges influences the coiledcoil protein structure. Molecular dynamics (MD) and free energy simulations with AMBER employed a particle mesh Ewald treatment of the electrostatics in explicit TIP3P solvent with balanced force field treatments. Preliminary studies with legacy force fields (ff94, ff96, ff99) show a profound instability of the coiled-coil structures in short MD simulation. Significantly better behavior is evident with the more balanced ff99SB and ff03 protein force fields. Overall, the results suggest that the coiled-coil structures can readily accommodate the larger acidic arginine or S-2,7-diaminoheptanedoic acid mutants in the salt bridge, whereas substitution of the smaller Lornithine residue leads to rapid disruption of the coiled-coil structure on the MD simulation time scale. This structural distortion of the secondary structure allows both the formation of large hydration pockets proximal to the charged groups and within the hydrophobic core. Moreover, the increased structural fluctuations and movement lead to a decrease in the water occupancy lifetimes in the hydration pockets. In contrast, analysis of the hydration in the stable dimeric coiled coils shows high occupancy water sites along the backbone residues with no water occupancy in the hydrophobic core, although transitory water interactions with the salt bridge residues are evident. The simulations of the fluorinated coiled-coils suggest that in some cases fluorination electrostatically stabilizes the intermolecular coiled-coil salt bridges. Structural analyses also reveal different side chain rotamer preferences for leucine compared to 5,5,5,5′,5′,5′-hexafluoroleucine mutants. These observed differences in the side chain rotamer populations * To whom correspondence should be addressed at the College of Pharmacy, University of Utah. Phone: (801) 587-9652, FAX: (801) 585-9119, e-mail: tec3@utah.edu. Supplementary MaterialSupplementary material is available that includes full sets of RMSd plots, results from force field comparisons, full description of new parameters, plots of water occupancy, more details regarding the free energy calculations, analysis of rotamer populations, and molecular graphics of the structural distortion in the ornithine substituted coiled-coil. suggest differential changes in the side chain conformational entropy upon coiled-coil formation when the protein is fluorinated. The free energy of hydration of the isolated 5,5,5,5′,5′,5′-hexafluoroleucine amino acid is calculated to be 1.1 kcal/mol less stable than leucine; this hydrophobic penalty in the monomer may ...

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“…Theoretical models have been suggested to describe the fusion mechanism based on the available experimental kinetic data (10)(11)(12). However, because of the large scale of the HA 2 rearrangement, only limited computational techniques, such as targeted molecular dynamics (13), have been applied to study the molecular details of the transition.…”

mentioning

confidence: 99%

Order and disorder control the functional rearrangement of influenza hemagglutinin

Lin

Eddy

Noel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre-and postfusion configurations of HA 2 , the membranefusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre-and postfusion crystallographic configurations of HA 2 . Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the "springloaded" model proposed for the HA 2 conformational transition.protein folding | structure-based model H emagglutinin (HA) is a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza virions into host cells (1). Structural rearrangements of HA during membrane fusion are crucial for the delivery of the viral genome. The postfusion conformation of HA shows considerable similarity to other viral fusion proteins and eukaryotic membrane receptors involved in intracellular vesicle trafficking (2), suggesting there may be common mechanisms in the function of these proteins. Therefore, HA may serve as a model system, allowing characterization of the molecular and energetic details that underlie its conformational transition to provide insights into general principles of membrane fusion (3).HA is a homotrimer consisting of two domains connected by disulfide bonds (4): a globular receptor binding domain (HA 1 ), and a coiled-coil membrane-fusion domain anchored to the viral membrane (HA 2 ). Recognized by the sialic acid receptor of a host cell, the intact virus enters the cell via endocytosis. Low pH in a late endosome then induces the dissociation of HA 1 from HA 2 (1) and an irreversible conformational transition of HA 2 . Experimentally, this conformational change can be triggered by either low pH, high temperature, or urea denaturation (5).Structures of HA in pre-and postfusion pH conformations have been solved by X-ray crystallography. The structure of the prefusion ectodomain contains both HA 1 and HA 2 , and was purified from influenza virions (4). A postfusion conformation of HA 1 and HA 2 were obtained from prefusion viral HA th...

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Investigation of Pathways for the Low-pH Conformational Transition in Influenza Hemagglutinin

Cited by 16 publications

References 62 publications

Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

Energetics of the loop‐to‐helix transition leading to the coiled‐coil structure of influenza virus hemagglutinin HA2 subunits

Molecular dynamics guided study of salt bridge length dependence in both fluorinated and non‐fluorinated parallel dimeric coiled‐coils

Order and disorder control the functional rearrangement of influenza hemagglutinin

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