Table of Contents
Biophysics 101 Genomics and Computational Biology
RNA2: Last week's take home lessons
Protein1: Today's story & goals
Palindromicity
Is there a code for protein interactions with DNA or RNA?
Interactions of Adjacent Basepairs in EGR1 Zinc Finger DNA Recognition
Motifs: weight all 64 Kaapp
Combinatorial arrays for binding constants
Ka apparent
DNA binding
A code for protein interactions with RNAs?
Protein1: Today's story & goals
Real world programming (3D + time)
Scary proteins
Protein programming time scales
What good are 3D protein structures?
Structure Based Drug Design
Covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance
3D structure & chemical genetics
Compensating steric hinderance in DNA polymerases
Real world programming with proteins
Protein1: Today's story & goals
Altered specificity mutants (continued)
SNPs & Covariance in proteins
Prediction of deleterious human alleles
Protein1: Today's story & goals
Oligonucleotide synthesis
Oligo -peptide & -nucleotide synthesis cycles
Nucleotide protecting groups
Modified backbones (for stability)
Biochemical diversity
Polyketide engineering
Non-computational interaction assays
Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors.
Protein1: Today's story & goals
Computational protein target selection
Given many genome sequences (of accuracy 99.99%)
Measuring 3D protein family relationships
Structural genomics projects
Programming cells via membrane proteins
Membrane protein 3D structures
Transmembrane prediction
"function from structure"
Where do 3D structures come from?
NMR distance-constrained ensembles Crystallographic phases & electron density
Crystallographic refinement
Crystallography & NMR System(CNS) X-plor
Measure Structure Quality
Protein1: Today's story & goals
20 Amino acids of 280
Favored peptide conformations
Molecular dynamics (Energy minimization, trajectories, approximations)
Molecular mechanics
Small protein molecular dynamics (only water as ligand)
Docking
Protein1: Today's story & goals
Top 10 drugs (20-42 M units/yr of 1.6 G units)
Estrogen Receptor DNA binding domain
Estrogen Binding Domain
Avoiding receptor cross-talk
A chemical switch for inhibitor-sensitive alleles of any protein kinase.
Protein1: Today's story & goals
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