Molecular dynamics simulation and experimental verification of the interaction between cyclin T1 and HIV-1 Tat proteins

Kaori Asamitsu; Takatsugu Hirokawa; Yurina Hibi; Takashi Okamoto

doi:10.1371/journal.pone.0119451

Molecular dynamics simulation and experimental verification of the interaction between cyclin T1 and HIV-1 Tat proteins

PLoS One. 2015 Mar 17;10(3):e0119451. doi: 10.1371/journal.pone.0119451. eCollection 2015.

Authors

Kaori Asamitsu¹, Takatsugu Hirokawa², Yurina Hibi¹, Takashi Okamoto¹

Affiliations

¹ Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
² Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Tokyo, Japan.

Abstract

The viral encoded Tat protein is essential for the transcriptional activation of HIV proviral DNA. Interaction of Tat with a cellular transcription elongation factor P-TEFb containing CycT1 is critically required for its action. In this study, we performed MD simulation using the 3D data for wild-type and 4CycT1mutants3D data. We found that the dynamic structural change of CycT1 H2' helix is indispensable for its activity for the Tat action. Moreover, we detected flexible structural changes of the Tat-recognition cavity in the WT CycT1 comprising of ten AAs that are in contact with Tat. These structural fluctuations in WT were lost in the CycT1 mutants. We also found the critical importance of the hydrogen bond network involving H1, H1' and H2 helices of CycT1. Since similar AA substitutions of the Tat-CycT1 chimera retained the Tat-supporting activity, these interactions are considered primarily involved in interaction with Tat. These findings described in this paper should provide vital information for the development of effective anti-Tat compound.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Binding Sites
Cyclin T / chemistry*
Cyclin T / metabolism
HIV-1 / chemistry
Molecular Dynamics Simulation*
Molecular Sequence Data
Protein Binding
tat Gene Products, Human Immunodeficiency Virus / chemistry*
tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Cyclin T
tat Gene Products, Human Immunodeficiency Virus

Grants and funding

This work was partially supported by grants form Grants-in-Aid from Research on HIV/AIDS, the Ministry of Health, Labour and Welfare of Japan, JSPS KAKENHI Grant Number 21390142, The IMAI MEMORIAL TRUST FOR AIDS RESEARCH, Grant-in-Aid for Research in Nagoya City University, and Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.