homo dimer structure prediction of bacterial signaling ... · mayu shibata:...
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Homo Dimer Structure Prediction of Bacterial Signaling Protein Utilizing Structural and Sequence Information
Mayu Shibata1, Xingcheng Lin2, Ryan R. Cheng2, José N. Onuchic21Department of Biology, Ochanomizu University, Tokyo, Japan. 2Center for Theoretical Biological Physics, Rice University, Ochanomizu University
Introduction
[1] AM Stock. (http://www3.cabm.rutgers.edu/faculty_and_research/stock.php)[2] Protein Data Bank. (http://www.rcsb.org)[3] SMOG. (http://smog-server.org)[2] R. Santos, F. Morcos, B. Jana, A. Andricopulo and J. Onuchic,
Scientific reports, 2015.
Results & Discussion
Cartoon schematic of bacterial TCS
Methodology
References
Acknowledgment• TOMODACHI STEM program is supported by a public-private partnership,
TOMODACHI Initiative• Host lab professor: José Onuchic• Mentors: Ryan Cheng and Xingcheng Lin• All the researchers, students and staffs of CTBP• Rice University• TOMODACHI STEM program staffs and participants
Structure Based Modeling(SBM)
Downloadcrystal structure
Calculate Potential using SMOG
Run simulation
couplings REC-REC Dimeric
REC-EFF Dimeric
REC-REC Monomeric
REC-EFF Monomeric
scheme1 ○ ー ー ー
scheme2 ○ ○ ー ー
scheme3 ○ ー ○ ー
scheme4 ○ ○ ○ ○
Add highly coevolving couplings into physical contacts
Frustration Analysis
Calculate local energetic frustration through Frustratometer Sever
Direct Coupling Analysis
Frustration Analysis
Discussion
Future works
• Infer homo dimeric structure of RR with two other EFF families
• DCA couplings well matched native structure
• DCA predicted additional coevolving pairs that were not seen in the native structure
• DCA couplings were seen in both REC-REC and REC-EFF areas
• The calculated frustration pattern was similar throughout native structure, highest RMSD structure and lowest RMSD structure
• Reasonable frustration pattern as a transcriptional factor
Structure of RR
Direct Coupling Analysis(DCA)
DownloadMSA
Pseudo-likelihood maximization DCA
highly coevolving couplings
REC-EFF couplings
REC-REC couplings
HK HKRR RR
RR RR
Background
Motivation
4 10 12Time (ns)
01020304050
RM
SD (Å
)
Scheme 4
0 2 6 8
4 10 12Time (ns)
1020304050
RM
SD (Å
)
Scheme 3
0 2 6 80
4 10 12Time (ns)
1020304050
RM
SD (Å
)
Scheme 2
0 2 6 80
4 10 12Time (ns)
1020304050
RM
SD (Å
)
Scheme 1
0 2 6 8
Two-component signaling (TCS) • A major mean of bacteria to sense and respond external stimuli• Consists of 2 proteins: Histidine Kinase (HK) + Response Regulator (RR)Response Regulator• Structures homo dimer to functions as a transcription factor• Consists of 2 domains: receiver domain (REC) + effector domain (EFF)• One of the 3 EFF families has anti-parallel homo dimeric structure
Structure Based Modeling
Filter couplings SASA > 50%
• Reproduce the anti-parallel dimer structure of the RR shown in prior research• Explore conformational landscape of bacterial homo dimer protein• Get deeper insights in bacterial gene expression to help drug designing
Contact map of native contacts and DCA couplings
• Scheme 4 had least fluctuation of all
• Scheme 4 showed various conformations of the dimer
• Predicted structures with high RMSD towards the native structure captured the conformational transition
Trajectory of RMSD with native structure
Some conformations in scheme4 step7
Lowest RMSDNative Highest RMSDHigh RMSD
Contact InformationMayu Shibata: [email protected]
• DCA predicted additional couplings in REC-REC and REC-EFF interactions as well as native contacts
• SBM-DCA simulations presented various conformations of RR homo dimer• Newly observed structures satisfy more monomeric and dimeric constraints
than native structure • Frustration analysis showed the predicted structures share similar
frustration pattern as the native one
0 50 100 150 2000
50
100
150
200
Highest RMSDNative
Structure and DCA constrains
Monomeric constraints within REC changed monomeric conformation and consequently dimeric conformation
Native