Howard University: Center for Computational Biology & Bioinformatics

Biochemistry & Molecular Biology

Chemistry NHGC Sys & Comp Science

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

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)

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

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

CCBB-HUNet Context…

CCBB Network Design…

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

Resource Sharing…

Statistical Genetics &

Bioinformatics

Center for Computational

Biology & Bioinformatics

Hardware

National Human Genome Center

Personnel Software

Resource Sharing… Cont’d

Computational

Proteomics

Center for Computational

Biology & Bioinformatics

Hardware

Department of Systems & Computer Sciences

Personnel Software

National Human Genome Center (NHGC)

General Clinical Research Center (GCRC)

Howard University Imaging Facility

Interaction With Other HU Facilities…

Imaging Informatics Support Activities…

Molecular design for targeted nanoparticles

Computational support for image resolution and refinement

GCRC NHGCCCBB

IT Support for CCBB, GCRC, and NHGC

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

Molecular Dynamics Simulation of Netropsin Binding to DNA: Genome-Base Drug Design

Netropsin

5’-CGCGAATTCGCG-3’********

3’-GCGCTTAAGCGC-5’

DNA

+

NetropsinN-terminal fragment of Moloney murine leukemia virus (NMLV) Reverse Transcriptase (RT)

5’-CTTAATTCGAATTAAG-3’3’-GAATTAAGCTTAATTC-5’

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

74.6870.8648.997 (Angstroms3) 6109 waters

Amidinium

Guanidinium

Binding Orientation5’-CTTAATTCGAATTAAG-3’ A G G A3’-GAATTAAGCTTAATTC-5’

Comparison of RMS deviation of free DNA and DNA in Complex

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

Width of the minor groove of DNA in complex with Netropsin

NT1

NT2

Dis 2

Dis 5

Dis 7

Dis 11

BII: 210 ≤ ε ≤ 300 and 150 ≤ ζ ≤ 210BI: 120 ≤ ε ≤ 210 and 235 ≤ ζ ≤ 295

DNA in Complex Free DNA

H-bond

NT1

NT2

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

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.

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

Thank you from….CCBB

Howard University