This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Madhusoodanan, M. Articles by Lazaridis, T. Search for Related Content PubMed PubMed Citation Articles by Madhusoodanan, M. Articles by Lazaridis, T.

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

Department of Chemistry, City College of the City University of New York, New York, New York 10031

Correspondence: Address reprint requests to Themis Lazaridis, Tel.: 212-650-8364; Fax: 212-650-6107; E-mail: themis{at}sci.ccny.cuny.edu.

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.