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PLoS ONE. Computational Studies on the Substrate Interactions of Influenza A Virus PB2 Subunit
[Source: PLoS ONE, full page: (LINK). Abstract, edited.]
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Computational Studies on the Substrate Interactions of Influenza A Virus PB2 Subunit
Ya-Jun Wang<SUP>1</SUP>, Jing-Fang Wang<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>*</SUP>, Jie Ping<SUP>1</SUP>, Yao Yu<SUP>2</SUP><SUP>,</SUP><SUP>4</SUP>, Ying Wang<SUP>1</SUP>, Peng Lian<SUP>1</SUP>, Xuan Li<SUP>2</SUP><SUP>,</SUP><SUP>4</SUP>, Yi-Xue Li<SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Pei Hao<SUP>2</SUP><SUP>,</SUP><SUP>5</SUP><SUP>*</SUP>
<SUP></SUP>
1 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China, 2 Shanghai Center for Bioinformation and Technology, Shanghai, China, 3 Bioinformatics Center, Key Laboratory of Systems Biology, Chinese Academy of Sciences, Shanghai, China, 4 Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China, 5 Institute of Pasteur, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Abstract
Influenza virus, which spreads around the world in seasonal epidemics and leads to large numbers of deaths every year, has several ribonucleoproteins in the central core of the viral particle. These viral ribonucleoproteins can specifically bind the conserved 3′ and 5′ caps of the viral RNAs with responsibility for replication and transcription of the viral RNA in the nucleus of infected cells. A fundamental question of most importance is that how the cap-binding proteins in the influenza virus discriminates between capped RNAs and non-capped ones. To get an answer, we performed molecular dynamics simulations and free energy calculations on the influenza A virus PB2 subunit, an important component of the RNP complexes, with a cap analog m7GTP. Our calculations showed that some key residues in the active site, such as Arg355, His357, Glu361 as well as Gln406, could offer significant hydrogen bonding and hydrophobic interactions with the guanine ring of the cap analog m7GTP to form an aromatic sandwich mechanism for the cap recognition and positioning in the active site. Subsequently, we applied this idea to a virtual screening procedure and identified 5 potential candidates that might be inhibitors against the PB2 subunit. Interestingly, 2 candidates Cpd1 and Cpd2 have been already reported to have inhibitory activities to the influenza virus cap-binding proteins. Further calculation also showed that they had comparatively higher binding affinities to the PB2 subunit than that of m7GTP. We believed that our findings could give an atomic insight into the deeper understanding of the cap recognition and binding mechanism, providing useful information for searching or designing novel drugs against influenza viruses.
Citation: Wang Y-J, Wang J-F, Ping J, Yu Y, Wang Y, et al. (2012) Computational Studies on the Substrate Interactions of Influenza A Virus PB2 Subunit. PLoS ONE 7(9): e44079. doi:10.1371/journal.pone.0044079
Editor: Hans-Joachim Wieden, University of Lethbridge, Canada
Received: November 24, 2011; Accepted: July 30, 2012; Published: September 5, 2012
Copyright: ? 2012 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the grants from the National Basic Research Program of China (973 Program, No. 2012CB517900), National Key Basic Research Program (No. 30800210), National Natural Science Foundation of China (Major Program, No. 90913009), Shanghai Pujiang Scholarship Program (No. 10PJ1408000), Doctoral Program Foundation of Institutions of Higher Education of China (No. 20110073120078), and China Postdoctoral Science Foundation (No. 20110490068). The authors gratefully acknowledge the support of SA-SIBS scholarship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: jfwang8113@sjtu.edu.cn (JFW); phao@sibs.ac.cn (PH)
-Ya-Jun Wang<SUP>1</SUP>, Jing-Fang Wang<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>*</SUP>, Jie Ping<SUP>1</SUP>, Yao Yu<SUP>2</SUP><SUP>,</SUP><SUP>4</SUP>, Ying Wang<SUP>1</SUP>, Peng Lian<SUP>1</SUP>, Xuan Li<SUP>2</SUP><SUP>,</SUP><SUP>4</SUP>, Yi-Xue Li<SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Pei Hao<SUP>2</SUP><SUP>,</SUP><SUP>5</SUP><SUP>*</SUP>
<SUP></SUP>
1 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China, 2 Shanghai Center for Bioinformation and Technology, Shanghai, China, 3 Bioinformatics Center, Key Laboratory of Systems Biology, Chinese Academy of Sciences, Shanghai, China, 4 Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China, 5 Institute of Pasteur, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Abstract
Influenza virus, which spreads around the world in seasonal epidemics and leads to large numbers of deaths every year, has several ribonucleoproteins in the central core of the viral particle. These viral ribonucleoproteins can specifically bind the conserved 3′ and 5′ caps of the viral RNAs with responsibility for replication and transcription of the viral RNA in the nucleus of infected cells. A fundamental question of most importance is that how the cap-binding proteins in the influenza virus discriminates between capped RNAs and non-capped ones. To get an answer, we performed molecular dynamics simulations and free energy calculations on the influenza A virus PB2 subunit, an important component of the RNP complexes, with a cap analog m7GTP. Our calculations showed that some key residues in the active site, such as Arg355, His357, Glu361 as well as Gln406, could offer significant hydrogen bonding and hydrophobic interactions with the guanine ring of the cap analog m7GTP to form an aromatic sandwich mechanism for the cap recognition and positioning in the active site. Subsequently, we applied this idea to a virtual screening procedure and identified 5 potential candidates that might be inhibitors against the PB2 subunit. Interestingly, 2 candidates Cpd1 and Cpd2 have been already reported to have inhibitory activities to the influenza virus cap-binding proteins. Further calculation also showed that they had comparatively higher binding affinities to the PB2 subunit than that of m7GTP. We believed that our findings could give an atomic insight into the deeper understanding of the cap recognition and binding mechanism, providing useful information for searching or designing novel drugs against influenza viruses.
Citation: Wang Y-J, Wang J-F, Ping J, Yu Y, Wang Y, et al. (2012) Computational Studies on the Substrate Interactions of Influenza A Virus PB2 Subunit. PLoS ONE 7(9): e44079. doi:10.1371/journal.pone.0044079
Editor: Hans-Joachim Wieden, University of Lethbridge, Canada
Received: November 24, 2011; Accepted: July 30, 2012; Published: September 5, 2012
Copyright: ? 2012 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the grants from the National Basic Research Program of China (973 Program, No. 2012CB517900), National Key Basic Research Program (No. 30800210), National Natural Science Foundation of China (Major Program, No. 90913009), Shanghai Pujiang Scholarship Program (No. 10PJ1408000), Doctoral Program Foundation of Institutions of Higher Education of China (No. 20110073120078), and China Postdoctoral Science Foundation (No. 20110490068). The authors gratefully acknowledge the support of SA-SIBS scholarship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: jfwang8113@sjtu.edu.cn (JFW); phao@sibs.ac.cn (PH)
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