Ron Levy group


Structural Bioinformatics II

Chemistry 5412

Spring 2017

Time and Location:

  • 5:30PM - 7:50OM, SERC 456



This course is designed to provide a basic introduction to computational methods used in protein structure determination and molecular modeling. The course emphasis will be on the use of computational methods for protein structure prediction to understand protein structures through modelling and on structure based drug design. The course will provide practical training in the application of modeling techniques in drug discovery

Reference Texts

  • Gregory A. Petsko, Dagmar Ringe, Protein Structure and Function, New Science Press, 2004
  • Thomas E. Creighton, Protein: Structure and Molecular properties , Freeman. W. H. & Company. 1992
  • Andrew Leach, Molecular Modelling: principles and Applications, Prentice Hall, 2001
  • Alan Hinchliffe, Molecular Modelling for Beginners, John Wiley & Sons, 2008
  • Hans-Dieter Holtje, Wolfgang Sippl, Didier Rognan, Gerd Folkers, Molecular Modeling: Basic Principles and Applications, Wiley-VCH Verlga GmbH, 2008
  • Daan Frenkel, Berend Smit, Understanding Molecular Simulation From Algorithms to Applications, Academic Press, 2001



I. Protein Structure Modelling

Dates Topics Lecturer Lecture Slides
1/23 Lecture:1
General overview on protein structure prediction
Strategies: ab initio vs knowledge-based
Secondary structure prediction
Community-wide assessment of protein structure
prediction CASP and CAMEO
Dr. Carnevale ppt
1/30 Lecture:2
Identifying templates for protein modelling:
Sequence alignment with BLAST and
position specific substitution matrices(PSI-BLAST)
Dr. Carnevale ppt
2/6 Lecture:3
Building a profile HMM from an alignment and
aligning sequences to it:
Formal definition of HMMs
Most probable state path: the Viterbi algorithm
The forward algorithm
Parameter estimation for HMMs
Dr. Carnevale ppt
2/13 Lecture:4
Potts Models and statistical inference of evolutionary sequence covariation Construction of Potts Models from MSAs Protein contact prediction Protein fitness Epistasis and the evolution of drug resistance
Dr. Haldane pdf
2/20 Lecture:5
Template based protein modelling
Homology modeling
Threading or Fold recognition
"Loop modelling"
Template Based and Non-Template Based Techniques
Dr. Dunbrack ppt
2/27 Lecture:6
Protein side chain modellingi
Graph based, Tree Decomposition, DEE, SCMF
Refinement of comparative models
Model quality assessment
Errors in protein modelling
Dr. Dunbrack ppt
3/6 Lecture:7(Protein Modelling Lab)
Hands on session in Protein Modelling(Rosetta/Modeller)
Dr. Dunbrack pdf

II. Molecular Modelling

Dates Topics Lecturer Lecture Slides
3/20 Lecture:8
Molecular Mechanics
Force fields: general features of molecular
mechanics, bonded terms, non-bonded terms,
and related parameterization strategy
Solvation effects: explicit and implicit models
Dr. Xia ppt
3/27 Lecture:9
Conformational Sampling Methods
Basics of Monte Carlo simulations: Metropolis algorithm
Basics of molecular dynamics simulations: Verlet algorithm
Introduction to maestro GUI package
Dr. Xia lecture and lab
4/3 lecture:10
Short lecture on Binding free energy calculations.
Hands on session of MD simulations
of ABL Kinase-Ligand interactions.
(Schrodinger package) Building the simulated
complex, energy minimization, adding
solvation models, molecular dynamics
(MD) simulations, post-simulation
analysis (Energy and structure fluctuations)
Dr. Xia lecture and lab

III. Structual Based Drug design

Dates Topics Lecturer Lecture Slides
4/10 Lecture:12
Virtual screening in Drug Discovery
Overview of ligand-based and structure-based screening,
basics of Molecular Docking.
Success stories form structure based drug design:
HIV-1 protease inhibitor.
Dr. Carnevale ppt
4/17 Lecture:13
Ligand-based screening:
pharmacophore based screening, Shape Based Screening
Dr. Gianti pdf
4/24 Lecture:14
Best practices in Virtual Screening:
ligand preparation, protein preparation,
benchmarking using various evaluation
metrics(ROC enrichment, RMSD for pose prediction)
Binding Free energy methods in Structure
Based Drug Design: the computation of binding
affinities relative and absolute
binding Free energy methods.
Dr. Gianti
5/1 Lecture:15(Docking and Binding Free Energy Calculation Lab)
Virtual Screening: Docking using Glide
(Schrodinger) Binding Free energy calculation
using the BEDAM workflow.The protein receptor
will be HIV-1 Integrase, and two ligands, one
binder and one non-binder will be used for ligands.
Dr. Carnevale