Question on restraint behavior when part of system decouples

From: Randy J. Zauhar (r.zauhar_at_usciences.edu)
Date: Mon Jan 29 2018 - 09:19:28 CST

Hi, I have always been troubled by the following aspect of the way constraints are applied in the typical ‘alchemical’ transformation when evaluating free energy of binding of ligand to protein.

1) If ligand is in complex with protein with restraints, and some restraints involve both ligand and protein atoms (say dihedral angle involving protein and ligand) and others only ligand atoms (say ligand RMSD), and the ligand is decoupled from the complex - do all restraint energy contributions ‘disappear’ during decoupling, or only the protein-ligand part, or do NONE of the contributions disappear? In the end, is the ligand effectively unrestrained in vacuum, or are the restraints still in place?

2) Similarly, when the ligand is decoupled from bulk solvent, why does the recommended protocol only restraint the conformation, why not position and and orientation as well, to mimic the loss of positional and rotational freedom that occurs upon complex formation? And again, if ligand in bulk decouples from solvent, is the end result a small molecule in vacuum, or a small molecule in vacuum with restraints? Those are very different situations!

I had assumed that the decoupling ONLY involved the nonbonded interactions between parts of the system, and that you needed to handle everything involving restraints via integration; but if that is so, my mental picture of how the thermodynamic cycle works is really off.

Thanks!

Randy

Randy J. Zauhar, PhD

Prof. of Biochemistry

Dept. of Chemistry & Biochemistry
University of the Sciences in Philadelphia
600 S. 43rd Street
Philadelphia, PA 19104

Phone: (215)596-8691
FAX: (215)596-8543
E-mail: r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu>

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