Course Description

A project-based introduction to computer-aided drug design tools and the principles behind them. Structural alignment and homology modeling. Molecular docking and molecular mechanics force fields for binding enthalpies. Continuum dielectric models of electrostatics and solvation. The Boltzmann distribution and alchemical binding free energy calculations. Quantitative structure property relationships. Business, legal, and ethical considerations of drug development.

Learning Objectives

The goals of this course are that you will be able to:

• Use Google Colab to run python computer code and to annotate results.
• Navigate directories, organize files, and execute programs on a command-line terminal.
• Recall the main types of biological macromolecules, identify their monomers, and describe their levels of structure.
• Describe the types of forces that maintain the structure of biological macromolecules and stabilize their interactions with small organic molecules.
• Visualize molecular structures with different styles. Compare the advantages and disadvantages of several styles.
• Align coordinates of protein structures with different amino acid sequences.
• Summarize the principles behind the main methods used to determine the structures of biological macromolecules. Compare their relative benefits and drawbacks.
• Predict protein structure based on the sequence of amino acids. Express confidence in the quality of a structure prediction.
• Analyze the prospects of a biological macromolecule (usually a protein) as a target for ligand design, from a community, scientific, and business perspective.
• Analyze an ethical issue related to pharmaceuticals.
• Predict the pKa’s of titratable amino acids on a protein and protonation at a given pH. Summarize the qualitative relationship between electrostatic potential and pKa.
• Compute and visualize the electrostatic potential of a protein. Compare the advantages and disadvantages of several representations.
• Perform a molecular docking calculation and visualize the results. Explain the limitations of molecular docking.
• Summarize the purpose of a molecular mechanics force field. Identify the terms in the molecular mechanics force field.
• Set up and perform a quantum mechanics/molecular mechanics simulation. Explain the concept of regions related to a QM/MM calculation. Compare and contrast QM/MM with molecular mechanics.
• Set up and perform a molecular dynamics simulation. Explain the key objectives of molecular simulation. Recall the purpose of key algorithms in molecular dynamics.
• Perform and interpret basic analyses of molecular dynamics simulations.
• Perform a binding free energy calculation. Explain key concepts related to binding free energy calculations. Compare and contrast molecular docking and binding free energy calculations.
• Develop a model for a quantitative structure-property relationship. Describe its domain of applicability.
• Propose and perform a rational series of calculations to explain or make predictions about a biological macromolecule. Manage and/or contribute to a team to complete the project.
• Present a polished scientific seminar reviewing a research area or describing new results.
• Present a scientific research poster.
• Write a coherent report meeting the standards of a peer-reviewed article in the scientific journal.

Prerequisite Knowledge

Organic chemistry (CHEM 237) is required. The following are helpful but not required: the Computer Science Requirement (CS 105/110/115), Introductory Biochemistry (BIOL 401), Molecular Biophysics (PHYS 410), and Physical Chemistry (CHEM 343 & CHEM 344).

iCourse Pilot

Chem 456 has been approved as iCourse. The iCourse pilot program allows for a project-based class to take the place of the IPRO graduation requirement. As the program is in the pilot stage, the procedure for obtaining IPRO credit is not automated.

Students should submit requests for IPRO credits through a petition in Degreeworks. On a student’s Degreeworks page, they need to click on the three-dot icon on the top right-hand side of the page. They will see “Petitions” in the drop-down menu and click on “Add a new petition”. The petition will go into a queue for UGAA to review.

Class Format

The class format will be hybrid synchronous. In addition to being in person, class session will be streamed live and also recorded on Zoom.

Classes will include lectures, exercises, presentations, a discussion, and quizzes.

Feel free to raise your hand and ask questions at any time during lecture. Chances are that if you have a question, somebody else will have the same one. At times, I will also ask you questions.

Most exercises will use Google Colab, which allows you to run computer code, view figures, annotate your results, and save data onto Google Drive, all within a web browser. The exercises run on the classroom computers and will mostly likely work on your personal computer. If you do not complete a exercise during class, you are expected to finish it for homework. For some longer calculations later in the semester, you will use ACCESS supercomputing resources.

Some class sessions will feature student presentations about projects. Presentations should make use of prepared slides. You should upload the slides as Powerpoint, Keynote, or PDF document to a folder on Google Drive before class and control them using my computer. Using my computer will make transitions between presenters more seamless. Presenters are expected to be able to present simultaneously in a classroom and via Zoom videoconference. Attendees are expected to be active participants by asking questions and contributing ideas. Both presenters and attendees may use extemporaneous drawings on whiteboards to illustrate thoughts as necessary. Presentations will be recorded on Zoom for members of the class to review.

There will be an ethics discussion.

Quizzes should be completed within the allotted time, 30 minutes.

Absences

Attendance at lectures and exercises is highly recommended but not required. If you need to miss them for any reason, you should watch the lecture recording online, complete any exercises, and contact me with specific questions.

If you need miss a presentation, discussion, or quiz, you should be excused. To be excused for illness or quarantine, you should contact student affairs. They will evaluate the situation and provide me with a recommendation about accommodating your circumstance. To be excused for sports, you should provide me with a note from your coach. If you are excused, we will discuss a way that you can make up for the absence.

Accounts

You should use your IIT Google account to run Google Colab notebooks and store data. If you have and use a personal Google account, you may run out of disk space.

Later in the semester, you will use ACCESS supercomputers. As ACCESS is not starting until September 1 (it is the successor of XSEDE), information about using the resource will be provided at a later time.