Download CMSE 520 BIOMOLECULAR STRUCTURE, FUNCTION AND

CMSE 520
BIOMOLECULAR STRUCTURE, FUNCTION
AND DYNAMICS
(Computational Structural Biology)
OUTLINE
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Review: Molecular biology
Proteins: structure, conformation and function(5 lectures)
Generalized coordinates, Phi, psi angles,
DNA/RNA: structure and function (3 lectures)
Structural and functional databases
(PDB, SCOP, CATH, Functional domain database, gene ontology)
Use scripting languages (e.g. python) to cross refernce between
these databases: starting from sequence to find the function
Relationship between sequence, structure and function
Molecular Modeling, homology modeling
Conservation, CONSURF
Relationship between function and dynamics
Confromational changes in proteins (structural changes due to ligation,
hinge motions, allosteric changes in proteins and consecutive function change)
Molecular Dynamics
Monte Carlo
Protein-protein interaction: recognition, structural matching, docking
PPI databases: DIP, BIND, MINT, etc...
References:
CURRENT PROTOCOLS IN BIOINFORMATICS (e-book)
(http://www.mrw.interscience.wiley.com/cp/cpbi/articles/bi0101/frame.html)
Andreas D. Baxevanis, Daniel B. Davison, Roderic D.M. Page, Gregory A. Petsko, Lincoln D. Stein, and
Gary D. Stormo (eds.) 2003 John Wiley & Sons, Inc.
INTRODUCTION TO PROTEIN STRUCTURE
Branden C & Tooze, 2nd ed. 1999, Garland Publishing
COMPUTER SIMULATION OF BIOMOLECULAR SYSTEMS
Van Gusteren, Weiner, Wilkinson
Internet sources
Ref: Department of Energy
Rapid growth in experimental technologies
Human Genome Projects
Two major goals
1. DNA mapping
2. DNA sequencing
Rapid growth in experimental technologies
z
Microrarray technologies – serial gene expression patterns and mutations
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Time-resolved optical, rapid mixing techniques - folding & function mechanisms (Æ
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Techniques for probing single molecule mechanics (AFM, STM) (Æ pN)
Æ more accurate models/data for computer-aided studies
Weiss, S. (1999). Fluorescence spectroscopy of single molecules.
Science 283, 1676-1683.
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function
Structural Biology/Molecular
Biophysics
Most (all?) basic “life processes” are
mediated by “machines” that represent
the ultimate miniaturization achievable
in a universe comprised of atoms and
molecules.
The goal is to understand the underlying
principles that govern the operation of
these molecular machines.
What th
is course is about
this
overview of ways in which computers
are used to solve problems in biology
supervised learning of illustrative or
frequently-used algorithms and
programs and databases
supervised learning of programming
techniques and algorithms selected
from these uses
Structure
What do the molecules look like?
How do we determine that experimentally?
Are there general structural principles?
How is this information organized?
How do structural generalizations relate to
simple physical/chemical principles?
Dynamics
Time is of the essence in biological
processes therefore how do we
understand time-dependent processes at
the molecular level?
How do we do this experimentally?
How do we do this computationally?
Promising Future for Computational Biology
Exponential growth in data
Sequence and structure data from experiments
Computational technology
12,665 structures as of July 11, 2000
22,810 structures as of October 7, 2003
35,026 structures as of February 7, 2006
Rost, B. (1998). Marrying structure and genomics.
Structure 6, 259-263
Large databases
Archival databanks of biological
information
Protein, DNA sequence databases
Protein structure and nucleic acid
databases
Protein expression patterns
Experimental
Tecniques
Derived databanks
Sequence motifs
Mutations and variations in proteins
Classifications and or relationships
Databanks of web sites
Databanks of databanks containing
biological information
Links between databanks
BIOINFORMATICS (definition)
Definition by Luscombe et al., Yale, Dept. of
Molecular Biophysics and Biochemistry, 2001
“Bioinformatics is conceptualizing biology in terms of
macromolecules (in the sense of physical chemistry)
and then applying ‘informatics’ techniques (derived
from disciplines such as applied maths, computer
science, and statistics) to understand and organize
the information associated with these molecules, on
a large-scale”
COMPUTATIONAL BIOLOGY (definition)
Definition by NIH (working definition)
The development and application of data-analytical and
theoretical methods, mathematical modeling and
computational simulation techniques
to the study of biological, behavioral, and social systems.
Information flow
A major task in computational molecular
biology is to “decipher” information
contained in biological sequences
Since the nucleotide sequence of a
genome contains all information
necessary to produce a functional
organism, we should in theory be able
to duplicate this decoding using
computers
http://www-fp.mcs.anl.gov/~gaasterland/sg-review-slides.html
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Two major challenges after completion of the HGP:
Structural Genomics and Functional Genomics
Schematic representation of the universe of proteins in a given organism
Kim, S.H. (1998). Nature Struct.Biol. 5, 643-645
Aim: “to construct the complete scheme of biological functions
and cellular pathways for the entire organism”
What's E-Cell Project?
E-Cell Project is an
international research
project aiming to model
and reconstruct
biological phenomena in
silico, and developing
necessary theoretical
supports, technologies
and software platforms
to allow precise whole
cell simulation.
Metabolism model of the model
cell constructed with 127 genes
PROTEOMICS
Covers the following areas (but not limited to):
¾Protein structure
Primary Structure: sequence of amino acids
Secondary Structure: local spatial arrangement
Tertiary Structure: three dimensional native conformation
¾Protein Function
related to 3-D shape of the protein
¾Protein clusters according to a specified characteristic
¾Protein-Protein Interaction
interaction among a number of proteins
¾Protein-DNA Interaction
interaction between one protein and the genome