Entropy for End-Point and FFT-Based Binding Free Energy Calculations

Information

  • Research Project
  • 10204042
  • ApplicationId
    10204042
  • Core Project Number
    R01GM127712
  • Full Project Number
    5R01GM127712-04
  • Serial Number
    127712
  • FOA Number
    PA-16-160
  • Sub Project Id
  • Project Start Date
    8/1/2018 - 5 years ago
  • Project End Date
    6/30/2022 - a year ago
  • Program Officer Name
    LYSTER, PETER
  • Budget Start Date
    7/1/2021 - 2 years ago
  • Budget End Date
    6/30/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    04
  • Suffix
  • Award Notice Date
    7/9/2021 - 2 years ago

Entropy for End-Point and FFT-Based Binding Free Energy Calculations

Project Summary Computers are often used to predict how tightly two molecules associate, their binding free energy. These predictions are helpful for designing drugs, predicting the consequences of genetic variation, and understanding how molecules interact to sustain life. Unfortunately, currently available methods are either fast or accurate, but not both. In general, fast methods do a poor job accounting for entropy, which is an important part of the free energy. The main objective of this project is to develop better ways to account for entropy in two popular techniques for studying molecular interactions: ?end-point? simulations of the bound complexes and their unbound counterparts; and molecular docking based on the Fast Fourier Transform. Speci?cally, new ways to analyze calculation results will be derived, implemented, assessed, and optimized. Additionally, the methods will be combined with enhanced sampling techniques. Our new end-point and FFT-based methods will be assessed by their ability to reproduce benchmark results from slower but more accurate computational methods, as well as experimental results. The benchmark dataset will include protein-ligand complexes and protein-protein complexes with known binding af?nities and crystal structures, as well as protein-protein complexes for which the effect of missense mutations on binding have been measured. We will also perform benchmark calculations on mutants of the tumor suppressor p53 that gain the ability to activate new proteins and promote tumor growth. In addition to serving as benchmarks, these calculations may provide mechanistic insight into how proteins bind various ligands and how p53 mutants gain new binding partners. Our new methods will also be tested in recurring community challenges: the ?Drug Design Data Resource? (D3R) grand challenge to predict protein-ligand complex structures and af?nities and the ?Critical Assessment of PRediction of Interactions? (CAPRI) challenge for protein-protein structure prediction. These blinded challenges will allow for an unbiased comparison of our methods to those from other research groups. Finally, we will assess our methods in a drug discovery project. We will use established methods and our new methods to virtually screen a chemical library against a pair of structurally similar bacterial metabolic enzymes. One enzyme is relevant to active and the other to dormant bacteria. Compounds predicted to selectively bind the bacterial (opposed to human) enzymes will be experimentally tested in biochemical assays. We anticipate that our improved methods will be signi?cantly more accurate than established approaches, advancing research ranging from interactome prediction to drug discovery.

IC Name
NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
  • Activity
    R01
  • Administering IC
    GM
  • Application Type
    5
  • Direct Cost Amount
    225000
  • Indirect Cost Amount
    109785
  • Total Cost
    334785
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    859
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIGMS:334785\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    MSFD
  • Study Section Name
    Macromolecular Structure and Function D Study Section
  • Organization Name
    ILLINOIS INSTITUTE OF TECHNOLOGY
  • Organization Department
    CHEMISTRY
  • Organization DUNS
    042084434
  • Organization City
    CHICAGO
  • Organization State
    IL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    606163717
  • Organization District
    UNITED STATES