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L03 pre-class assignment

Due: Sep 11, 2024 by 1:00 p.m. Points: 15

Please read the selected paper below and answer the following questions in your own words. I am only looking for a few sentences per question. Write your answers in your favorite Word processing software and submit them as a PDF to gradescope.

Paper: Champion, C., Gall, R., Ries, B., Rieder, S. R., Barros, E. P., & Riniker, S. (2023). Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases. Journal of Chemical Information and Modeling, 63(22), 7133-7147. DOI: 10.1021/acs.jcim.3c01469

Tip

Do not get too bogged down by the methodology. Your instructor will go over the following topics in the respective lecture.

  1. Molecular Dynamics (MD) Simulations:
    • Basic principle: computer simulation of physical movements of atoms and molecules
    • Applications in computational biology and drug discovery
  2. Force Fields:
    • Definition: set of parameters used to calculate the potential energy of a system of atoms
    • Examples mentioned in the paper: GAFF and OpenFF
  3. Free Energy Calculations:
    • Importance in drug discovery (predicting binding affinities)
    • Brief overview of traditional methods like Free Energy Perturbation (FEP) and Thermodynamic Integration (TI)
  4. Alchemical Transformations:
    • Concept of "morphing" one molecule into another in silico
    • Why it's useful for calculating relative binding free energies
  5. Sampling in MD Simulations:
    • Importance of exploring conformational space
    • Challenges with traditional methods (e.g., getting "stuck" in local energy minima)
  6. Enhanced Sampling Techniques:
    • General concept of improving exploration of conformational space
    • Brief mention of replica exchange as an example

Q01

What is the main goal or purpose of this study?

Q02

The authors applied RE-EDS to four different kinase systems. List these kinases and briefly describe the types of ligand modifications studied for each.

Q03

What two small molecule force fields were used in this study? Why do you think the authors chose to use multiple force fields?

Q04

Briefly explain the concept of "hybrid topology" used in this paper. How does it differ from "dual topology"?

Q05

What metric did the authors use to assess the accuracy of their binding free energy calculations? What value is considered the threshold for "chemical accuracy"?

Q06

For which kinase system did RE-EDS perform best? For which did it perform worst? What factors may have contributed to these differences?

Q07

What were some of the key limitations or challenges identified for the RE-EDS method?

Q08

Based on the results, what are the potential applications or benefits of using RE-EDS for drug discovery?

Q09

What questions do you have about the paper?