Publication
Title
Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART)
Author
Abstract
Cosolvent molecular dynamics (MD) simulations are molecular dynamics simulations used to identify preferable locations of small organic fragments on a protein target. Most cosolvent molecular dynamics workflows make use of only water-soluble fragments, as hydrophobic fragments would cause lipophilic aggregation. To date the two approaches that allow usage of hydrophobic cosolvent molecules are to use a low (0.2 M) concentration of hydrophobic probes, with the disadvantage of a lower sampling speed, or to use force field modifications, with the disadvantage of a difficult and inflexible setup procedure. Here we present a third alternative, that does not suffer from low sampling speed nor from cumbersome preparation procedures. We have built an easy-to-use open source command line tool PART (Plumed Automatic Restraining Tool) to generate a PLUMED file handling all intermolecular restraints to prevent lipophilic aggregation. We have compared restrained and unrestrained cosolvent MD simulations, showing that restraints are necessary to prevent lipophilic aggregation at hydrophobic probe concentrations of 0.5 M. Furthermore, we benchmarked PART generated restraints on a test set of four proteins (Factor-Xa, HIV protease, P38 MAP kinase and RNase A), showing that cosolvent MD with PART generated restraints qualitatively reproduces binding features of cocrystallised ligands.
Language
English
Source (journal)
Journal of Cheminformatics
Publication
2024
ISSN
1758-2946
DOI
10.1186/S13321-024-00819-Y
Volume/pages
16 :1 (2024) , p. 1-11
Article Reference
23
ISI
001171784900001
Pubmed ID
38414037
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Fragment-based computational design of inhibitors of dipeptidyl peptidase 8 and 9.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Record
Identifier
Creation 27.02.2024
Last edited 02.04.2024
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