Qinghua Wang - Academia.edu (original) (raw)

Papers by Qinghua Wang

Bulletin of the American Physical Society, 2017

hemagglutinin (HA), a surface glycoprotein responsible for the entry and replication of flu virus... more hemagglutinin (HA), a surface glycoprotein responsible for the entry and replication of flu viruses in their host cells, functions by starting a dramatic conformational rearrangement, which leads to a fusion of the viral and endosomal membranes. It has been claimed that a loop-to-coiled-coil transition of the B-loop domain of HA drives the HA-induced membrane fusion. On the lack of dynamical details, however, the microscopic picture for this proposed "spring-loaded" movement is missing. To elaborate on the transition of the B-loop, we performed a set of unbiased all-atom molecular dynamics simulations of the full B-loop structure with the CHARMM36 force field. The complete free-energy profile constructed from our simulations reveals a slow transition rate for the B-loop that is incompatible with a downhill process. Additionally, our simulations indicate two potential sources of kinetic traps in the structural switch of the B-loop: Desolvation barriers and non-native secondary structure formation. The slow timescale of the B-loop transition also confirms our previous discovery from simulations using a coarse-grained structure-based model, which identified two competitive pathways both with a slow B-loop transition for HA to guide the membrane fusion.

Virology, 2018

Influenza pandemic occurs when a new strain from other animal species overcomes the interspecies ... more Influenza pandemic occurs when a new strain from other animal species overcomes the interspecies barriers and supports rapid human-to-human transmission. A critical prerequisite to this process is that hemagglutinin (HA) acquires a few key mutations to switch from avian receptors to human receptors. Previous studies suggest that H1 and H2/H3 HAs use different sets of mutations for the switch. This report shows that HA from the 1918 H1N1 pandemic virus (1918H1 HA) adopts the set of mutations used by H2/H3 HAs in receptor-preference switch when its 130-loop is made similar to those of H2/H3 HAs. Thus, the 130-loop appears to be the key determinant for the different mutations employed by pandemic H1 or H2/H3 HA. The correlation of the mutational routes and the 130-loop as unraveled in this study opens the door for efficient investigation of mutations required by other HA subtypes for inter-human airborne transmission.

Influenza: Current Research, 2016

Influenza viruses are important pathogens responsible for flu epidemics and pandemics. The socioe... more Influenza viruses are important pathogens responsible for flu epidemics and pandemics. The socioeconomic impact of seasonal flu is very significant and the rapid rate of virus evolution necessitates the development of new vaccines every year. Another major challenge is the emergence of novel strains that are highly pathogenic for humans. Examples include H7N9 and H5N1 (emerged from birds) which have mortality rates of up to 30% and 60%, respectively. Research is underway to develop of a universal flu vaccine that would provide long-lasting protection and be effective against emergent strains. Following on from their highly-acclaimed 2010 book, Drs. Wang and Tao present a new, up-to-date and comprehensive review of current advancements in molecular influenza virology. Topics covered include: stem-specific broadly neutralizing antibodies to the virus hemagglutinin; virus replication and transcription; influenza B virus hemagglutinin; influenza A virus ribonucleoprotein complex; regulation of the virus replication machinery by host factors; evolution of receptor specificity of influenza A virus hemagglutinin: PB1-F2, a multi-functional non-structural influenza A virus protein; and avian influenza H7N9 virus. Highly informative and well referenced, this book is essential reading for all influenza specialists and is recommended reading for all virologists, immunologists, molecular biologists, public health scientists and research scientists in pharmaceutical companies.

Proceedings of the National Academy of Sciences, 2018

SignificanceInfluenza hemagglutinin (HA) is the viral membrane protein that guides entry of flu v... more SignificanceInfluenza hemagglutinin (HA) is the viral membrane protein that guides entry of flu viruses into host cells. A global refolding of the stem domain of HA,HA2, is crucial to successful viral membrane fusion, but the molecular mechanism relating this conformational change ofHA2to its fusogenic properties remains unclear. We use molecular dynamics simulations to quantify the thermodynamic importance of the B loop domain for driving the overallHA2rearrangement. We find that the B loop’s loop-to-coiled-coil refolding is not strongly downhill and thus is a possible target for therapeutics. A buried hydrophilic amino acid is implicated in destabilizing the coiled coil, and the sequence divergence at this position may indicate functional differences between group 1 and 2 HAs.

Journal of Medical Virology, 2008

The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or i... more The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.

PLoS ONE, 2009

The Pandemic (H1N1) 2009 is spreading to numerous countries and causing many human deaths. Althou... more The Pandemic (H1N1) 2009 is spreading to numerous countries and causing many human deaths. Although the symptoms in humans are mild at present, fears are that further mutations in the virus could lead to a potentially more dangerous outbreak in subsequent months. As the primary immunity-eliciting antigen, hemagglutinin (HA) is the major agent for hostdriven antigenic drift in A(H3N2) virus. However, whether and how the evolution of HA is influenced by existing immunity is poorly understood for A(H1N1). Here, by analyzing hundreds of A(H1N1) HA sequences since 1918, we show the first evidence that host selections are indeed present in A(H1N1) HAs. Among a subgroup of human A(H1N1) HAs between 1918,2008, we found strong diversifying (positive) selection at HA 1 156 and 190. We also analyzed the evolutionary trends at HA 1 190 and 225 that are critical determinants for receptor-binding specificity of A(H1N1) HA. Different A(H1N1) viruses appeared to favor one of these two sites in host-driven antigenic drift: epidemic A(H1N1) HAs favor HA 1 190 while the 1918 pandemic and swine HAs favor HA 1 225. Thus, our results highlight the urgency to understand the interplay between antigenic drift and receptor binding in HA evolution, and provide molecular signatures for monitoring future antigenically drifted 2009 pandemic and seasonal A(H1N1) influenza viruses.

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bioRxiv, 2021

The world is experiencing an unprecedented coronavirus disease 2019 (COVID-19) pandemic caused by... more The world is experiencing an unprecedented coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 spike protein-based vaccines are currently the main preventive agent to fight against the virus. However, several variants with extensive mutations in SARS-CoV-2 spike proteins have emerged. Some of these variants exhibited increased replication, higher transmission and virulence, and were partially resistant to antibody neutralization from natural infection or vaccination. With over 130 million confirmed cases and widespread vaccination around the globe, the emergence of new escape SARS-CoV-2 variants could be accelerated. New therapeutics insensitive to mutations are thus urgently needed. Here we have developed an inhibitor based on SARS-CoV-2 spike protein that potently reduced pseudovirus infectivity by limiting the level of SARS-CoV-2 spike proteins on virion envelope. Most importantly, the inhibitor was equal...

PLOS ONE, 2019

Globally, human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract i... more Globally, human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in newborns, young children, and the elderly for which there is no vaccine. The RSV fusion (F) glycoprotein is a major target for vaccine development. Here, we describe a novel monoclonal antibody (designated as R4.C6) that recognizes both prefusion and post-fusion RSV F, and binds with nanomole affinity to a unique neutralizing site comprised of antigenic sites II and IV on the globular head. A 3.9 Å-resolution structure of RSV F-R4.C6 Fab complex was obtained by single particle cryo-electron microscopy and 3D reconstruction. The structure unraveled detailed interactions of R4.C6 with antigenic site II on one protomer and site IV on a neighboring protomer of post-fusion RSV F protein. These findings significantly further our understanding of the antigenic complexity of the F protein and provide new insights into RSV vaccine design.

We report a C-atom-based scoring function, named OPUS-CSF, for ranking protein structural models.... more We report a C-atom-based scoring function, named OPUS-CSF, for ranking protein structural models. Rather than using traditional Boltzmann formula, we built a scoring function (CSF score) based on the native distributions (analyzed through entire PDB) of coordinate components of mainchain C atoms on selected residues of peptide segments of 5, 7, 9, and 11 residues in length. In testing OPUS-CSF on decoy recognition, it maximally recognized 257 native structures out of 278 targets in 11 commonly used decoy sets, significantly more than other popular all-atom empirical potentials. The average correlation coefficient with TM-score was also comparable with those of other potentials. OPUS-CSF is a highly coarse-grained scoring function, which only requires input of partial mainchain information, and very fast. Thus it is suitable for applications at early stage of structural building.

Journal of molecular biology, Jan 29, 2017

We report a new distance- and orientation-dependent, all-atom statistical potential derived from ... more We report a new distance- and orientation-dependent, all-atom statistical potential derived from side-chain packing, named OPUS-DOSP, for protein structure modeling. The framework of OPUS-DOSP is based on OPUS-PSP, previously developed by us (JMB (2008) 376, 288-301), with refinement and new features. In particular, distance or orientation contribution is considered depending on the range of contact distance. A new auxiliary function in energy function is also introduced, in addition to the traditional Boltzmann term, in order to adjust the contributions of extreme cases. OPUS-DOSP was tested on 11 decoy sets commonly used for statistical potential benchmarking. Among 278 native structures, 239 and 249 native structures were recognized by OPUS-DOSP without and with the auxiliary function respectively. The results show that OPUS-DOSP has an increased decoy recognition capability comparing with those of other relevant potentials to date.

The journal of physical chemistry. B, Jan 19, 2016

Hemagglutinin (HA), the membrane-bound fusion protein of the Influenza virus, enables the entry o... more Hemagglutinin (HA), the membrane-bound fusion protein of the Influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, explicit-solvent molecular dynamics simulations were employed to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt-bridge between the N-terminus of HA stem domain and Asp1122 locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order-disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence ...

Acta crystallographica. Section D, Biological crystallography, 2015

In macromolecular X-ray crystallography, building more accurate atomic models based on lower reso... more In macromolecular X-ray crystallography, building more accurate atomic models based on lower resolution experimental diffraction data remains a great challenge. Previous studies have used a deformable elastic network (DEN) model to aid in low-resolution structural refinement. In this study, the development of a new refinement algorithm called the deformable complex network (DCN) is reported that combines a novel angular network-based restraint with the DEN model in the target function. Testing of DCN on a wide range of low-resolution structures demonstrated that it constantly leads to significantly improved structural models as judged by multiple refinement criteria, thus representing a new effective refinement tool for low-resolution structural determination.

Proceedings of the National Academy of Sciences of the United States of America, Jan 13, 2015

Leiomodin (Lmod) is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mut... more Leiomodin (Lmod) is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mutations, deletion, or instability are linked to lethal nemaline myopathy. However, the lack of high-resolution structures of Lmod nucleators in action severely hampered our understanding of their essential cellular functions. Here we report the crystal structure of the actin-Lmod2162-495 nucleus. The structure contains two actin subunits connected by one Lmod2162-495 molecule in a non-filament-like conformation. Complementary functional studies suggest that the binding of Lmod2 stimulates ATP hydrolysis and accelerates actin nucleation and polymerization. The high level of conservation among Lmod proteins in sequence and functions suggests that the mechanistic insights of human Lmod2 uncovered here may aid in a molecular understanding of other Lmod proteins. Furthermore, our structural and mechanistic studies unraveled a previously unrecognized level of regulation in mammalian signal tran...

PLOS ONE, 2015

In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. ... more In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA 1 Q226, the triad of HA 1 S137, E190 and G228 in GD H6 HA allows the binding to both avian-and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA 1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA 1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.

Proceedings of the National Academy of Sciences of the United States of America, Jan 19, 2014

Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes ... more 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 HA2, the membrane-fusion 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 HA2. 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...

Virology, 2013

Influenza A and B viruses are responsible for the severe morbidity and mortality worldwide in ann... more Influenza A and B viruses are responsible for the severe morbidity and mortality worldwide in annual influenza epidemics. Currently circulating influenza B virus belongs to the B/Victoria or B/Yamagata lineage that was diverged from each other about 30-40 years ago. However, a mechanistic understanding of their divergent evolution is still lacking. Here we report the crystal structures of influenza B/ Yamanashi/166/1998 hemagglutinin (HA) belonging to B/Yamagata lineage and its complex with the avian-like receptor analogue. Comparison of these structures with those of undiverged and diverged influenza B virus HAs, in conjunction with sequence analysis, reveals the molecular basis for the divergent evolution of influenza B virus HAs. Furthermore, HAs of diverged influenza B virus strains display much stronger molecular interactions with terminal sialic acid of bound receptors, which may allow for a different tissue tropism for current influenza B viruses, for which further investigation is required.

Protein Science, 1999

GroEL minichaperones have potential in the biotechnology industry for the refolding of recombinan... more GroEL minichaperones have potential in the biotechnology industry for the refolding of recombinant proteins. With the aim of enhancing and widening their use, we have created two highly stable functional variants of minichaperone GroEL~193-345!. A sequence alignment of 130 members of the chaperonin 60~Cpn60! family was used to design 37 single mutations. Two small-to-large mutations, A223T, A223V and one similar-size mutation, M233L, all located in the hydrophobic core were found to stabilize the protein by more than 1 kcal mol Ϫ1 each. Six stabilizing mutations were combined, yielding two multiple mutants that were 6.99 and 6.15 kcal mol Ϫ1 more stable than wild-type protein. Even though some of the substituted residue pairs are close to each other in the protein structure, the energetic effects of mutation are approximately additive. In particular, the stabilizing substitution A223T is unexpected and would have been missed by purely structural analysis. In the light of previously reported successes employing similar methods with several other proteins, our results show that a homology based approach is a simple and efficient method of increasing the stability of a protein.

Proceedings of the National Academy of Sciences, 2007

Receptor-binding specificity of HA, the major surface glycoprotein of influenza virus, primarily ... more Receptor-binding specificity of HA, the major surface glycoprotein of influenza virus, primarily determines the host ranges that the virus can infect. Influenza type B virus almost exclusively infects humans and contributes to the annual “flu” sickness. Here we report the structures of influenza B virus HA in complex with human and avian receptor analogs, respectively. These structures provide a structural basis for the different receptor-binding properties of influenza A and B virus HA molecules and for the ability of influenza B virus HA to distinguish human and avian receptors. The structure of influenza B virus HA with avian receptor analog also reveals how mutations in the region of residues 194 to 196, which are frequently observed in egg-adapted and naturally occurring variants, directly affect the receptor binding of the resultant virus strains. Furthermore, these structures of influenza B virus HA are compared with known structures of influenza A virus HAs, which suggests t...