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.

Learning Objectives

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

• Use Jupyter notebooks to run python computer code and to annotate results.
• Navigate directories, organize files, and execute programs on a Linux command-line terminal.
• Perform calculations on a computing cluster.
• 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.
• Use generative AI methods to predict the structure of protein complexes 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 human health, scientific, and business perspective.
• Explain basics of G protein-coupled receptor pharmacology, including pharmacodynamic parameters and functional selectivity.
• 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.
• Perform a virtual screening of a chemical library based on 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 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 free energy calculation. Explain key concepts related to free energy calculations.
• Develop a model for a quantitative structure-property relationship. Describe its domain of applicability.
• 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.
• 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.
• Write a coherent report meeting the standards of a peer-reviewed article in the scientific journal.

Prerequisite Knowledge

Organic Chemistry (CHEM 237) and Physical Chemistry I: Thermodynamics (CHEM 343) are required. The following are helpful but not required: the Computer Science Requirement (CS 105/110/115) and Introductory Biochemistry (BIOL 401).

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 Jupyter notebooks, which allow you to run computer code, view figures, annotate your results, and save data, all within a web browser. The exercises run on ACCESS-CI computing resources, which you can access through the classroom computers and likely 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 submit batch jobs to ACCESS-CI. Unless otherwise specified, exercises will be due one week after they are assigned.

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 Microsoft OneDrive 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.

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

Absences

Attendance at lectures is highly recommended and required to earn participation points (see “Grading” below). If you need to miss a lecture for any reason, you should watch the recording online. When I ask questions to the class, try to pause the recording and answer them yourself before moving ahead to the answer. Contact me with any specific questions that you have. You may have a number of unexcused absences from lectures without directly affecting your grade. However, I strongly discourage you from habitually skipping class. Students who do so often do not pass and rarely do well.

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 will need an ACCESS-CI account, so you should sign up. Once you’ve signed up, let me know you account name so I can provide you access to an allocation for high-performance computing resources.

You should use your IIT Microsoft account to upload files to MS OneDrive.