Why Do We Need Alchemical Methods to Compute Gibbs Energy Changes?

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SUMMARY

Alchemical methods are essential for accurately computing Gibbs energy changes in molecular dynamics simulations, particularly for ligand binding to proteins. Simply averaging Gibbs energies from separate simulations of the free ligand and protein, and the protein-ligand complex, fails to account for critical entropic contributions. This oversight results in an incomplete understanding of the free energy landscape, which is vital for accurate modeling in computational chemistry.

PREREQUISITES
  • Understanding of Gibbs energy and its significance in thermodynamics
  • Familiarity with molecular dynamics simulations
  • Knowledge of entropic contributions in free energy calculations
  • Experience with alchemical methods in computational chemistry
NEXT STEPS
  • Research alchemical free energy calculations using tools like GROMACS or AMBER
  • Study the role of entropy in molecular binding processes
  • Explore advanced molecular dynamics techniques for accurate free energy estimation
  • Learn about the differences between enthalpy and free energy in chemical systems
USEFUL FOR

This discussion is beneficial for computational chemists, molecular modelers, and researchers involved in drug design and protein-ligand interactions.

MichaelWiteman
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Hi,

To compute, for example, the Gibbs energy change for a ligand binding to a protein, various so called alchemical methods are used in molecular dynamics simulations. My question is why can't we just obtain averaged Gibbs energies for 1) the free ligand and protein in the same water box, and 2) the protein-ligand complex in the water box and then subtract? Both cases will have the same amount and type of atoms and the simulation would be conducted at the same temperature, density etc. I know this is a naive question but understanding the reasons why this is not done will help me understand a few things.

Thanks!

--Mike
 
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I believe you will be missing all entropic contribution. Your suggestions can account for the energy but not for the free energy.
 

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