Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART)
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 l...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Cheminformatics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13321-024-00819-y |
| _version_ | 1827326388331347968 |
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| author | Olivier Beyens Hans De Winter |
| author_facet | Olivier Beyens Hans De Winter |
| author_sort | Olivier Beyens |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:43:45Z |
| format | Article |
| id | doaj.art-7cdf005b3f8f4c859640cf37f7efde90 |
| institution | Directory Open Access Journal |
| issn | 1758-2946 |
| language | English |
| last_indexed | 2024-03-07T14:43:45Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Cheminformatics |
| spelling | doaj.art-7cdf005b3f8f4c859640cf37f7efde902024-03-05T20:06:08ZengBMCJournal of Cheminformatics1758-29462024-02-0116111110.1186/s13321-024-00819-yPreventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART)Olivier Beyens0Hans De Winter1Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of AntwerpLaboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of AntwerpAbstract 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.https://doi.org/10.1186/s13321-024-00819-yMolecular dynamicsCosolvent simulationsMetadynamicsConformational samplingDrug design |
| spellingShingle | Olivier Beyens Hans De Winter Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) Journal of Cheminformatics Molecular dynamics Cosolvent simulations Metadynamics Conformational sampling Drug design |
| title | Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) |
| title_full | Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) |
| title_fullStr | Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) |
| title_full_unstemmed | Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) |
| title_short | Preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using Plumed Automatic Restraining Tool (PART) |
| title_sort | preventing lipophilic aggregation in cosolvent molecular dynamics simulations with hydrophobic probes using plumed automatic restraining tool part |
| topic | Molecular dynamics Cosolvent simulations Metadynamics Conformational sampling Drug design |
| url | https://doi.org/10.1186/s13321-024-00819-y |
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