Binding pocket dynamics along the recovery stroke of human β-cardiac myosin.
The druggability of small-molecule binding sites can be significantly affected by protein motions and conformational changes. Ligand binding, protein dynamics and protein function have been shown to be closely interconnected in myosins. The breakthrough discovery of omecamtiv mecarbil (OM) has led t...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-05-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1011099 |
| _version_ | 1797802632380678144 |
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| author | Fariha Akter Julien Ochala Arianna Fornili |
| author_facet | Fariha Akter Julien Ochala Arianna Fornili |
| author_sort | Fariha Akter |
| collection | DOAJ |
| description | The druggability of small-molecule binding sites can be significantly affected by protein motions and conformational changes. Ligand binding, protein dynamics and protein function have been shown to be closely interconnected in myosins. The breakthrough discovery of omecamtiv mecarbil (OM) has led to an increased interest in small molecules that can target myosin and modulate its function for therapeutic purposes (myosin modulators). In this work, we use a combination of computational methods, including steered molecular dynamics, umbrella sampling and binding pocket tracking tools, to follow the evolution of the OM binding site during the recovery stroke transition of human β-cardiac myosin. We found that steering two internal coordinates of the motor domain can recapture the main features of the transition and in particular the rearrangements of the binding site, which shows significant changes in size, shape and composition. Possible intermediate conformations were also identified, in remarkable agreement with experimental findings. The differences in the binding site properties observed along the transition can be exploited for the future development of conformation-selective myosin modulators. |
| first_indexed | 2024-03-13T05:09:38Z |
| format | Article |
| id | doaj.art-1c30bbcbd22e421e8fdd01da318d4cca |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-03-13T05:09:38Z |
| publishDate | 2023-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-1c30bbcbd22e421e8fdd01da318d4cca2023-06-16T05:30:41ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582023-05-01195e101109910.1371/journal.pcbi.1011099Binding pocket dynamics along the recovery stroke of human β-cardiac myosin.Fariha AkterJulien OchalaArianna ForniliThe druggability of small-molecule binding sites can be significantly affected by protein motions and conformational changes. Ligand binding, protein dynamics and protein function have been shown to be closely interconnected in myosins. The breakthrough discovery of omecamtiv mecarbil (OM) has led to an increased interest in small molecules that can target myosin and modulate its function for therapeutic purposes (myosin modulators). In this work, we use a combination of computational methods, including steered molecular dynamics, umbrella sampling and binding pocket tracking tools, to follow the evolution of the OM binding site during the recovery stroke transition of human β-cardiac myosin. We found that steering two internal coordinates of the motor domain can recapture the main features of the transition and in particular the rearrangements of the binding site, which shows significant changes in size, shape and composition. Possible intermediate conformations were also identified, in remarkable agreement with experimental findings. The differences in the binding site properties observed along the transition can be exploited for the future development of conformation-selective myosin modulators.https://doi.org/10.1371/journal.pcbi.1011099 |
| spellingShingle | Fariha Akter Julien Ochala Arianna Fornili Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. PLoS Computational Biology |
| title | Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. |
| title_full | Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. |
| title_fullStr | Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. |
| title_full_unstemmed | Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. |
| title_short | Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. |
| title_sort | binding pocket dynamics along the recovery stroke of human β cardiac myosin |
| url | https://doi.org/10.1371/journal.pcbi.1011099 |
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