DNA -> RNA -> Proteins Proteins are central to life Cellular structure, communications, etc. Medical, drug development Failure -> disease (ex: missing, misfolding) The key to protein function is structure

Structure Representation (Protein) CPK: hard sphere modelBall-and-stickCartoon Patrice Koehl

Proteins Sequence QKPFQCRICM RNFSRSDHLT THIRTHTG >7million sequences Structure 65,000 structures

From Sequence to Function and Back… KKAVINGEQIRSISDLHQTLKK WELALPEYYGENLDALWDCLTG VEYPLVLEWRQFEQSKQLTENG AESVLQVFREAKAEGCDITI Sequence Structure Function Evolution ligand The Cycle of Life Patrice Koehl

Protein: Linear chain of amino acids called residues (4 in this toy protein) Ser Trp Leu O N N N N O O C C C C O O CαCα CαCα CαCα CαCα Lys H H H H H The backbone (red) is the same for all residues. The side-chains (green) vary.

Polar Amino acids C CH2 C CA CB CG CD NE2 NH2O OE1 Glutamine Patrice Koehl

C CH2 C CH C CA CB CG CD1 CE1 CZCE2 CD2 OH Polar Amino acids Patrice Koehl Tyrosine

How a Protein Takes Shape Patrice Koehl, UC Davis,

Energy Landscape Unfolded State Expanded, disordered Molten Globule Compact, disordered Native State Compact, Ordered Barrier Height 1 ms to 1s 1  s Barrier crossing time ~ exp[Barrier Height] Patrice Koehl

Some applications of Bioinformatics Find genes Predict protein docking Protein design: drug development Cancer Flu

Interface: 1AKJ ligand (green) and receptor (blue): Protein Docking

Protein design Engineer to bind to radioactive isotope

What Is Cancer?

Loss of Normal Growth Control Cancer cell division Fourth or later mutation Third mutation Second mutation First mutation Uncontrolled growth Cell Suicide or Apoptosis Cell damage— no repair Normal cell division

Example of Normal Growth Cell migration Dermis Dividing cells in basal layer Dead cells shed from outer surface Epidermis

The Beginning of Cancerous Growth Underlying tissue

Tumors (Neoplasms) Underlying tissue

Invasion and Metastasis 3 Cancer cells reinvade and grow at new location 1 Cancer cells invade surrounding tissues and blood vessels 2 Cancer cells are transported by the circulatory system to distant sites

Malignant versus Benign Tumors Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis

What Causes Cancer? Some viruses or bacteria Heredity Diet Hormones RadiationSome chemicals

Use Machine Learning to Detect Gene Interactions Why find gene interactions? diagnosis of disease genes code for proteins: hope to gain knowledge of biochemical pathways in disease

Test data with different gene and gene pairs perturbed to unmutated 1. Training step: weights are adjusted to predict cancer Test data 2. Predict step: genes 2 and 7 interact? P0P0 P 2, P 7, P 2,7 3. Apply Metric: If (P 0 - P 2,7 ) = (P 0 - P 2 ) + (P 0 - P 7 ) then additive model, no interactions.

Viruses Viruses on the attac on the attac Flu Attack! How A Virus Invades Your BodyFlu Attack! How A Virus Invades Your Body