Protein Modeling in Education:

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Protein Modeling in Education
A protein experiment for teaching
George D. Purvis III CAChe Group,
Fujitsu Beaverton, Oregon Nigel
Richards University of Florida Gainesville,
Florida
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Teaching with Laboratory exercises
1 Calculating the Geometry of Molecules and
Ions 2 Kinetics of Substitution Reactions 3
Sunscreen and Ultraviolet Absorption 4
Conformations of Menthone and Isomenthone 5 The
Evelyn Effect 6 Prediction of Aromatic
Substitution Rates 7 Resonance Stabilization 8
Vibrational Analysis of Halogen Hydrides 9
Rotational Barrier in N-N-dimethylacetamide 10
Polarities of Small Molecules 11 Structures of
Molecules which Exceed the Octet 12 Gas Phase
Acidities of Binary Hydrogen Compounds 13 Crystal
Lattices and Close Packing Sites 14
Identification and Execution of Symmetry
Operations 15 Infrared Spectra and Molecular
Geometry 16 MOs of Simple Molecules 17 MOs of
Second Period Diatomic Molecules 18 MOs of
Octahedral Transition Metal Complexes 19 Relative
Ligand Field Strengths 20 Stereoselectivity of
Chiral Chelating Ligands
Student Crispin Wong and Prof. James
Currie Pacific University 20 Experiments in
General, Organic, Physical, Inorganic
Download free from http//www.CACheSoftware.com
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Changing face of chemistry

• Arguably, more than half of all industrial
  chemists in the US are now employed in
  pharmaceuticals, biotechs or related business
• Knowledge of protein structure and function is
  exploding
• PDB in 1990 200 structures vs 18,000 today
• Students are excited about the biotech century
• General chemistry incorporating biochemistry
• Biochemistry replacing general chemistry as first
  course in chemistry

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Learning problems

• What does a protein look like?
• Which side is the front?
• Whats wrong with a crystal structure?
• How is sequence related to 3D structure?
• Whats an active site?
• What are conserved residues?
• What is meant by complementarity in docking?

Words are not enough. Pictures and exploration
are needed.
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Four protein exercises free

• Importing and cleaning proteins
• What does a protein look like?
• Whats wrong with the crystal structure?
• Charges?
• Viewing and analyzing proteins and ligands
• How is sequence related to structure?
• What is an active site?
• Docking ligands into proteins
• What is meant by complementarity in docking?
• Discovering an active site from a homolog
• What is a conserved residue?

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Curriculum applications

• Medicinal chemistry graduate course
• Beginning medical school course in molecular
  medicine
• Protein engineering course
• Molecular modeling course
• Workshops on drug discovery and design
• Introductory biochemistry course

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University of California, Fullerton
Prof. Kantardjieff used these exercises in her
summer high school research program
Katherine Kantardjieff ProfessorPhysical
ChemistryUniversity of California,
FullertonDirector of the W.M. Keck Foundation
Center for Molecular Structure
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A real world problem TBCould a drug be
developed that would be effective against TB?

• TB kills millions each year and it has been
  estimated that one-third of the worlds
  population is infected with latent TB
• TB expresses purine nucleoside phosphorylase
  (PNP) which catalyzes the phosphorolysis of
  purine nucleotides to purine bases and
  deoxynucleosides to (deoxy)ribosyl 1-phosphate
• Inhibition of TB-PNP may make TB latent
• Humans also express PNP

ImmH
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1. Importing and cleaning proteins
ImmH
1G20 TB-PNP
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2. Viewing and analyzing proteins and ligands
Active site pocket
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3. Docking ligands into proteins
ImmH
PNP030
Farutin, V., Masterson, L., Andricopulo, A.D.,
Cheng, J., Riley, B., Hakimi, R., Frazer, J. W.,
and Cordes, E. H., Structure-Activity
Relationships for a Class of Inhibitors of Purine
Nucleoside Phosphorylase, J. Med. Chem., 1999,
42, 2422-2431.
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4. Discovering an active site from a homolog
binding site?
Binding site
Crevice map of 1ULA human PNP
1ULA human PNP
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Evaluating mastery

• Importing and cleaning proteins
• Given a new structure from the PDB, students
  display a unique feature of the protein.
• Viewing and analyzing proteins and ligands
• Given a protein with a bound ligand, students
  display a map of the pocket and discuss the
  ligand binding
• Docking ligands into proteins
• Given a unique ligand from the PNP library,
  students dock it into TB-PNP by superposition.
• Discovering an active site from a homolog
• Students identify an active site in other PNP
  homologs.

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Student response

• Learning curve next to nil
• High school students worked through the exercises
  their first week and were actively conducting
  research on novel ligands within a week.
• Translates words into pictures
• Whats the front?
• Sequence view powerful
• Homology and secondary structure were easy to
  understand.
• Site license eliminates barriers
• Students can work at home

Katherine KantardjieffProfessorUC, Fullerton
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Site License - the Freedom to Learn

• Any place
• laboratory, dorm, home, office, library
• Mac or PC
• Any time
• at midnight, before exams, at the last minute
• Any one
• students, faculty, staff

Learning without barriers
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Availability of the laboratory

• Free
• PDF files and starting structures
• Pre-release NOW http//www.CACheSoftware.com/prot
  einexp
• Release Jan, 2003 with CAChe ActiveSite
  functionality

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SUNY Oneonta
I think it is fair to say that we can no longer
operate our curriculum without access to
modeling. The license plays a key role in the
education of our students at all levels.
John C. Kotz, Distinguished Teaching Professor
SUNY College of Oneonta
We have had a CAChe site license for two years
(and had the Worksystem for some years before
that). We have devised two laboratory experiments
for general chemistry that allow students to use
the system to discover for themselves the nature
of molecular structure. You can find these on our
webpages In the first experiment students build
several series of related molecules, measuring
the bond angles in each. From this they
essentially construct the VSEPR theory
themselves. We do the experiment before they have
been introduced to structural principles in
lectures. The first time we did this I was amazed
at how quickly they recognized the fundamental
structural principles. The second experiment is a
more advanced experiment, done while we are
lecturing on hybridization, formal charge, double
bond rigidity, and so on. Each experiment can be
done in a 2-3 hour time period.