The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant

Samuel Genheden, Oliver Kuhn, Paulius Mikulskis, Daniel Hoffmann, Ulf Ryde

Research output: Contribution to journalArticlepeer-review

839 Downloads (Pure)

Abstract

We have performed a systematic study of the entropy term in the MM/GBSA (molecular Mechanics combined with generalized Born and surface area solvation) approach to calculate ligand-binding affinities The entropies are calculated by a normal mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with. distances. larger than 8-16 angstrom to the ligand, including a 4 angstrom shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the Whole protein within statistical uncertainty (172 kJ/mol). We have also tested to use a distance dependent dielectric constant in the minimization and. frequency calculation (epsilon = 4r), but it typically gives slightly different entropies and poorer binding, affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 angstrom) and epsilon =1 Such an approach also gives an improved precision for the calculated binding free energies.
Original languageEnglish
Pages (from-to)2079-2088
JournalJournal of Chemical Information and Modeling
Volume52
Issue number8
DOIs
Publication statusPublished - 2012

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)

Subject classification (UKÄ)

  • Theoretical Chemistry

Fingerprint

Dive into the research topics of 'The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant'. Together they form a unique fingerprint.

Cite this