Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool
We present the software package transformato for the setup of large-scale relative binding free energy calculations. Transformato is written in Python as an open source project (https://github.com/wiederm/transformato); in contrast to comparable tools, it is not closely tied to a particular molecula...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.954638/full |
| _version_ | 1811268407532716032 |
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| author | Johannes Karwounopoulos Johannes Karwounopoulos Marcus Wieder Stefan Boresch |
| author_facet | Johannes Karwounopoulos Johannes Karwounopoulos Marcus Wieder Stefan Boresch |
| author_sort | Johannes Karwounopoulos |
| collection | DOAJ |
| description | We present the software package transformato for the setup of large-scale relative binding free energy calculations. Transformato is written in Python as an open source project (https://github.com/wiederm/transformato); in contrast to comparable tools, it is not closely tied to a particular molecular dynamics engine to carry out the underlying simulations. Instead of alchemically transforming a ligand L1 directly into another L2, the two ligands are mutated to a common core. Thus, while dummy atoms are required at intermediate states, in particular at the common core state, none are present at the physical endstates. To validate the method, we calculated 76 relative binding free energy differences ΔΔGL1→L2bind for five protein–ligand systems. The overall root mean squared error to experimental binding free energies is 1.17 kcal/mol with a Pearson correlation coefficient of 0.73. For selected cases, we checked that the relative binding free energy differences between pairs of ligands do not depend on the choice of the intermediate common core structure. Additionally, we report results with and without hydrogen mass reweighting. The code currently supports OpenMM, CHARMM, and CHARMM/OpenMM directly. Since the program logic to choose and construct alchemical transformation paths is separated from the generation of input and topology/parameter files, extending transformato to support additional molecular dynamics engines is straightforward. |
| first_indexed | 2024-04-12T21:21:16Z |
| format | Article |
| id | doaj.art-37be5c662e234375872c7476cc7f90ac |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-12T21:21:16Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-37be5c662e234375872c7476cc7f90ac2022-12-22T03:16:17ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-09-01910.3389/fmolb.2022.954638954638Relative binding free energy calculations with transformato: A molecular dynamics engine-independent toolJohannes Karwounopoulos0Johannes Karwounopoulos1Marcus Wieder2Stefan Boresch3Faculty of Chemistry, Institute of Computational Biological Chemistry, University of Vienna, Vienna, AustriaVienna Doctoral School of Chemistry (DoSChem), University of Vienna, Vienna, AustriaDepartment of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, Vienna, AustriaFaculty of Chemistry, Institute of Computational Biological Chemistry, University of Vienna, Vienna, AustriaWe present the software package transformato for the setup of large-scale relative binding free energy calculations. Transformato is written in Python as an open source project (https://github.com/wiederm/transformato); in contrast to comparable tools, it is not closely tied to a particular molecular dynamics engine to carry out the underlying simulations. Instead of alchemically transforming a ligand L1 directly into another L2, the two ligands are mutated to a common core. Thus, while dummy atoms are required at intermediate states, in particular at the common core state, none are present at the physical endstates. To validate the method, we calculated 76 relative binding free energy differences ΔΔGL1→L2bind for five protein–ligand systems. The overall root mean squared error to experimental binding free energies is 1.17 kcal/mol with a Pearson correlation coefficient of 0.73. For selected cases, we checked that the relative binding free energy differences between pairs of ligands do not depend on the choice of the intermediate common core structure. Additionally, we report results with and without hydrogen mass reweighting. The code currently supports OpenMM, CHARMM, and CHARMM/OpenMM directly. Since the program logic to choose and construct alchemical transformation paths is separated from the generation of input and topology/parameter files, extending transformato to support additional molecular dynamics engines is straightforward.https://www.frontiersin.org/articles/10.3389/fmolb.2022.954638/fullfree energymolecular dynamics simulationbinding affinityautomated setupopen sourcepython (programming language) |
| spellingShingle | Johannes Karwounopoulos Johannes Karwounopoulos Marcus Wieder Stefan Boresch Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool Frontiers in Molecular Biosciences free energy molecular dynamics simulation binding affinity automated setup open source python (programming language) |
| title | Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool |
| title_full | Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool |
| title_fullStr | Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool |
| title_full_unstemmed | Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool |
| title_short | Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool |
| title_sort | relative binding free energy calculations with transformato a molecular dynamics engine independent tool |
| topic | free energy molecular dynamics simulation binding affinity automated setup open source python (programming language) |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.954638/full |
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