howard university: center for computational biology and bioinformatics
TRANSCRIPT
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Howard University: Center for Computational Biology & Bioinformatics
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Biochemistry & Molecular Biology
Chemistry NHGC Sys & Comp Science
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Historical Development of the CCBB…
1995 Faculty Research Laboratory
1997 Laboratory of Molecular Computations (LMC)
2003 Laboratory of Molecular Computations & Bioinformatics (LMCB)
2006 Center for Computational Biology & Bioinformatics (CCBB)
1989 Faculty Research Laboratory
MD/MM
MD/MM, QSAR
MD/MM, QSAR
MD/MM, QSAR, Comp. Chemistry, Statistical Genetics & Bioinformatics
MD/MM, QSAR, Comp. Chemistry, Statistical Genetics & Bioinformatics, other
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Rationale and Need for the CCBB
1. Encourage the interaction among mathematicians, scientists (biomedical, chemists, biologists, physicists, engineers), and computer-based scientists in the resolution of complex disease processes.
2. Encourage multi-disciplinary approaches to research.
The Howard University Strategic Framework for Action II (SFAII)
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CCBB Resident Personnel… 2003-2008
Dr. William M. Southerland Professor & DirectorMolecular modelingmolecular dynamics
Dr. Zengjian Hu Res. Assistant ProfessorMolecular modelingmolecular dynamicsvirtual database development virtual ligand screening
Dr. Yayin Fang Res. Assistant Professor Molecular dynamicsab initio calculations.
Dr. Qingqi YueResearch Associate Analysis of genetic data and computer programming for genetics data analysis.
Mr. Joseph Gill Research Assistant Computer science, hardware cluster development
Mr. Guy Lingani Lab/IT Manager System/network administrator Laboratory Manager
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CCBB Compute Resources
Resource Type Processors # of
Nodes # of CPU's
YearInstalle
d Gflops
SGI Origin 200 Rack Mounted 180 MHz 3 6 2000 2.16SGI Indigo2 (joy2) 75 MHz 1 1 2002 0.15SGI Indigo (joy) 75 MHz 1 1 2002 0.15SGI Octane2 (joy4) 195 MHz 2 2 2002 0.78SGI Octane2 (joy5) 250 MHz 2 3 2002 1SGI Tezro dual cpu's 800 MHz 3 6 2004 9.6SGI Fuel 800 MHz 1 1 2004 1.6Linux Cluster dual cpu's (biocluster) 3.20 GHz 7 14 2004 89.6Linux Cluster (Bio2001 & Bio2003) 3.20 GHz 2 4 2004 25.6Linux Quad Cluster Dual CPU’s (bee) 3.20 GHz 7 56 2006 291.2Linux cluster (elephant) 3.20 GHz 1 4 2007 25.6
30 Nodes 98 CPU 's
447.44 Total
Gflops
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CCBB-HUNet Context…
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CCBB Network Design…
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Center for Computational Biology & Bioinformatics… (CCBB)
Protein targeted drug design
Genome based drug designNew biomaterial design
Prediction of protein inter-residue contact clusters maps
Classification of protein folds
Prediction of domain boundaries in proteinsDevelopment of inter-residues contacts
database
Virtual high throughput ligand screening@Howard University, Medicinal Chemistry, Pharmacology, Dentistry, Cancer Center, Systems & Computer Sciences
Indiana University-Purdue University Indianapolis, Texas A&M University-Corpus Christi
Statistical genetics
QSAR structure design
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Resource Sharing…
Statistical Genetics &
Bioinformatics
Center for Computational
Biology & Bioinformatics
Hardware
National Human Genome Center
Personnel Software
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Resource Sharing… Cont’d
Computational
Proteomics
Center for Computational
Biology & Bioinformatics
Hardware
Department of Systems & Computer Sciences
Personnel Software
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National Human Genome Center (NHGC)
General Clinical Research Center (GCRC)
Howard University Imaging Facility
Interaction With Other HU Facilities…
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Imaging Informatics Support Activities…
Molecular design for targeted nanoparticles
Computational support for image resolution and refinement
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GCRC NHGCCCBB
IT Support for CCBB, GCRC, and NHGC
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Example of Research project
Barnase thermal titration Via MD simulation – detection of early denaturation sites
3D-QSAR study of novel anticonvulsant enaminones
Salvianolic acid B as a targeting agent for development of a Cox-2 targeted therapy for drug resistant head and neck cancer
Small Molecule DNA Recognition
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Molecular Dynamics Simulation of Netropsin Binding to DNA: Genome-Base Drug Design
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Netropsin
5’-CGCGAATTCGCG-3’********
3’-GCGCTTAAGCGC-5’
DNA
+
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NetropsinN-terminal fragment of Moloney murine leukemia virus (NMLV) Reverse Transcriptase (RT)
5’-CTTAATTCGAATTAAG-3’3’-GAATTAAGCTTAATTC-5’
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Free DNA
Free Netrospin
DNA Netrospin complex
16 base pairs of d(CTTAATTCGAATTAAG)2
Netropsin molecule only
Two netropsin molecules bound in the minor groove of DNA d(CTTAATTCGAATTAAG)2
Systems calculated
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74.6870.8648.997 (Angstroms3) 6109 waters
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Amidinium
Guanidinium
Binding Orientation5’-CTTAATTCGAATTAAG-3’ A G G A3’-GAATTAAGCTTAATTC-5’
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Comparison of RMS deviation of free DNA and DNA in Complex
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Definition of the width of DNA minor groove
Closest distance between two phosphates on different strands of DNA cross the minor groove.
Dis1
Dis2
Dis3
Dis4
Dis5
Dis6
Dis7
Dis8
Dis9
Dis10
Dis11
Dis12
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Width of the minor groove of DNA in complex with Netropsin
NT1
NT2
Dis 2
Dis 5
Dis 7
Dis 11
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BII: 210 ≤ ε ≤ 300 and 150 ≤ ζ ≤ 210BI: 120 ≤ ε ≤ 210 and 235 ≤ ζ ≤ 295
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DNA in Complex Free DNA
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H-bond
NT1
NT2
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Binding Energy
EComplex EDNA-Free ENetropsin-Free E
1690.17 4533.28 -10.964 -2821.18
E = EComplex – EDNA-Free – 2*ENetropsin-Free
EComplex EDNA-In-Complex ELigand-In-Complex E
1690.17 4516.13 38.97 -2864.93
E = EComplex – EDNA-In-Complex –E(NT1+NT2)-In-Complex
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Summary
1. Molecular dynamic simulation show that the properties of the ligand and DNA contribute to the DNA-ligand binding.
2. The study can be used to design and develop new anti-tumor agent that will be able to selectively bound to the specific A/T or, in the future, G/C rich regions of DNA.
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Acknowledgements…This work is supported by 2 G12 RR003048 from the RCMI Program, Division of Research Infrastructure, National Center for Research Resources, NIH
Dr. William M Southerland Dr. Legand BurgeDr. Vernon R. Morris Dr. Chunmei LiuDr. Zengjian Hu Dr. Eugene BilliotMr. Guy Lingani Dr. Qingqi YueDr. George Bonney Dr. Angela JacksonDr. Eric C. Long Dr. Kenneth R. ScottDr. Xinbin Gu Dr. Patrice JacksonDr. Tadasha Culbreath Mr. Donnell Scott
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Thank you from….CCBB
Howard University