Free energy along drug-protein binding pathways interactively sampled in virtual reality
We describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art iMD-VR framework to generate a diverse range of protein-ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FE methods. To investigate the performance of the method, we apply iMD-VR-FE to investigate the unbinding of a benzamidine ligand from a trypsin protein. The binding free energy calculated using iMD-VR-FE is similar for each pathway, indicating internal consistency. Moreover, the resulting free energy profiles can distinguish energetic differences between pathways corresponding to various protein-ligand conformations (e.g., helping to identify pathways that are more favourable) and enable identification of metastable states along the pathways. The two-step iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses for candidate pathways in biomolecular systems, quickly obtaining both qualitative and quantitative insight..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
arXiv.org - (2023) vom: 21. Nov. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Deeks, Helen M. [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
http://dx.doi.org/10.1038/s41598-023-43523-x |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XAR041707710 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | XAR041707710 | ||
| 003 | DE-627 | ||
| 005 | 20231201080420.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231201s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a http://dx.doi.org/10.1038/s41598-023-43523-x |2 doi | |
| 035 | |a (DE-627)XAR041707710 | ||
| 035 | |a (arXiv)2311.17925 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Deeks, Helen M. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Free energy along drug-protein binding pathways interactively sampled in virtual reality |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a We describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art iMD-VR framework to generate a diverse range of protein-ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FE methods. To investigate the performance of the method, we apply iMD-VR-FE to investigate the unbinding of a benzamidine ligand from a trypsin protein. The binding free energy calculated using iMD-VR-FE is similar for each pathway, indicating internal consistency. Moreover, the resulting free energy profiles can distinguish energetic differences between pathways corresponding to various protein-ligand conformations (e.g., helping to identify pathways that are more favourable) and enable identification of metastable states along the pathways. The two-step iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses for candidate pathways in biomolecular systems, quickly obtaining both qualitative and quantitative insight. | ||
| 650 | 4 | |a Physics - Chemical Physics |7 (dpeaa)DE-84 | |
| 650 | 4 | |a Physics - Biological Physics |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 530 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Zinovjev, Kirill |4 aut | |
| 700 | 1 | |a Barnoud, Jonathan |4 aut | |
| 700 | 1 | |a Mulholland, Adrian J. |4 aut | |
| 700 | 1 | |a van der Kamp, Marc W. |4 aut | |
| 700 | 1 | |a Glowacki, David R. |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t arXiv.org |g (2023) vom: 21. Nov. |
| 773 | 1 | 8 | |g year:2023 |g day:21 |g month:11 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-023-43523-x |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u https://arxiv.org/abs/2311.17925 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XAR | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 21 |c 11 | ||