CS273CS273Algorithms for Structure and Algorithms for Structure and
Motion in BiologyMotion in BiologyInstructors:
Serafim Batzoglou and Jean-Claude Latombe
Teaching Assistant: Sam Gross
| serafim | latombe | ssgross | @ cs.stanford.edu
Spring 2006 – http://www.stanford.edu/class/cs273/
Need a Scribe!!
Range of Bio-CS InteractionRange of Bio-CS Interaction
Gene
Molecules
Tissue/Organs
Body system
Robotic surgery
Molecular structures,similaritiesand motions
Soft-tissue simulation andsurgical trainingCells
Simulation ofcell interaction
CS273Sequencealignment
Enormous range over space and time
Focus on Proteins
Proteins are the workhorses of all living organisms
They perform many vital functions, e.g:• Catalysis of reactions• Transport of molecules• Building blocks of muscles• Storage of energy• Transmission of signals• Defense against intruders
Proteins are also of great interest from a computational
viewpoint They are large molecules (few 100s
to several 1000s of atoms) They are made of building blocks
(amino acids) drawn from a small “library” of 20 amino-acids
They have an unusual kinematic structure: long serial linkage (backbone) with short side-chains
Proteins are associated with many challenging
problems Predict folded structures and motion pathways Understand why some proteins misfold or
partially fold, causing such diseases as: cystic fibrosis, Parkinson, Creutzfeldt-Jakob (mad cow)
Find structural similarities among proteins and classify proteins
Find functional structural motifs in proteins Predict how proteins bind against other proteins
and smaller molecules Design new drugs Engineer and design proteins and protein-like
structures (polymers)
Central Dogma Central Dogma of Molecular Biologyof Molecular Biology
Central Dogma Central Dogma of Molecular Biologyof Molecular Biology
transcription
translation
Protein SequenceProtein Sequence
O
N
NN
N
OO
O
Long sequence of amino-acids (dozens to thousands), also called residues
Dictionary of 20 amino-acids (several billion years old)
(residue i-1)
O
N
NN
N
OO
O
Protein SequenceProtein Sequence
Peptide bond(partial double bond character)
T
Central Dogma Central Dogma of Molecular Biologyof Molecular Biology
Physiological conditions: aqueous solution, 37°C, pH 7,atmospheric pressure
Levels of Protein StructuresLevels of Protein Structures
hemoglobin (4 polypeptide chains)
Quaternary
Mostly -helicesMostly -sheets
Mixed
Intermediate states
FoldingFoldingUnfolded (denatured) state
Folded (native) state
Many pathways
http://www-shakh.harvard.edu/ProFold2.html
How (we think) a protein folds ...
G = H - TS
http://www-shakh.harvard.edu/ProFold2.html
How (we think) a protein folds ...
G = H - TS
http://www-shakh.harvard.edu/ProFold2.html
How (we think) a protein folds ...
G = H - TS
http://www-shakh.harvard.edu/ProFold2.html
How (we think) a protein folds ...
G = H - TS
http://www-shakh.harvard.edu/ProFold2.html
How (we think) a protein folds ...
G = H - TS
Motion of Proteins Motion of Proteins in Folded Statein Folded State
HIV-1 protease
Structural variability of the overall ensemble of native ubiquitin structures
[Shehu, Kavraki, Clementi, 2005]
Amylosucrase
Flexible Loop
Loop 7
Central Dogma Central Dogma of Molecular Biologyof Molecular Biology
BindingBinding
Inhibitor binding to HIV protease
Protein-protein binding
Ligand-protein binding
Binding of Pyruvate to LDH
(reduction of pyruvate to lactase)
ASP-195HIS-193
ASP-166
ARG-169
+
+
+
THR-245
C
C
OO
O
CH3
NADH
GLN-101
ARG-106Loop
Lactate dehydrogenase environment
Pyruvate
Nicotinamide adenine dinucleotide (coenzyme)
What is CS273 about?What is CS273 about?
Algorithms and computational schemes for molecular biology problems
Molecular biology seen by computer scientists
y = f(x)
Biologists like experiments, specifics and classifications
They like it better to know many (xi,yi) – i.e., facts – and classify them, than to know f
Computer scientists like simulation, abstractions, and general algorithms
They want to know f – the explanation of the facts – and efficient ways to compute it, but rarely care for any (xi,yi)
One challenge of Computational Biology is to fuse these two cultures
The Shock of Two Cultures
Two Views of a BioComputation Class
Where are IT resources for biology available and how to use them
How to design efficient data structures and algorithms for biology
Main Ideas Behind CS273Main Ideas Behind CS2731. The information is in the sequence
Sequence Structure (shape) Function Sequence similarity Structural/functional similarity Sequences are related by evolution
Main Ideas Behind CS273Main Ideas Behind CS2731. The information is in the sequence
Sequence Structure (shape) Function Sequence similarity Structural/functional similarity Sequences are related by evolution
2. Biomolecules move and bind to achieve their functions Deformation folded structures of proteins Motion + deformation multi-molecule complexes One cannot just “jump” from sequence to function
Protein folding
Ligandprotein binding
Sequence Structure Function
sequencesimilarity
structuresimilarity
Main Ideas Behind CS273Main Ideas Behind CS2731. The information is in the sequence
Sequence Structure (shape) Function Sequence similarity Structural/functional similarity Sequences are related by evolution
2. Biomolecules move and bind to achieve their functions Deformation folded structures of proteins Motion + deformation multi-molecule complexes One cannot just “jump” from sequence to function
CS273 is about algorithms for sequence, structure and
motion- Finding sequence and shape similarities- Relating structure to function- Extracting structure from experimental data - Computing and analyzing motion pathways
Vision Underlying CS273 Goal of computational biology:
Low-cost high-bandwidth in-silico biology
Requirements:Reliable models Efficient algorithms
Algorithmic efficiency by exploiting properties of molecules and processes: Proteins are long kinematic chains Atoms cannot bunch up together Forces have relatively short ranges
Computational Biology is more than using computers to biological problems or mimicking nature (e.g., performing MD simulation)
Tentative Schedule Tentative Schedule 1 April 5 Introduction
2 April 10 Protein geometric and kinematic models
3 April 12 Conformational space
4 April 17 Inverse kinematics and applications
5 April 19 Sequence similarity
6 April 24 Sequence similarity
7 April 26 Sequence similarity
8 May 1 Structure comparison9 May 3 Structure comparison10 May 8 Protein phylogeny, clustering, and
classification11 May 10 Protein phylogeny, clustering, and
classification12 May 15 Energy maintenance
13 May 17 Energy maintenance
14 May 22 Structure prediction
15 May 24 Roadmap methods
16 May 31 Structure prediction
17 June 5 Structure prediction
18 June 7 TBA
19 June 12 Project presentations (2 hours)
Instructors and TAsInstructors and TAs
Instructors:– Serafim Batzoglou – Jean-Claude Latombe
TA:– Sam Gross
Emails: | serafim | latombe | ssgross | @ cs.stanford.edu
Class website: http://cs273.stanford.edu
Expected Work
Regular attendance to lectures and active participation
Class scribing (assignments will depend on # of students)
Exciting programming project:http://www.stanford.edu/class/cs273/project/project.html - Structure prediction
- Clustering and distance metrics- Protein design- Something else
Questions?Questions?