Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel
Mechanosensitive channel of large conductance (MscL) detects and responds to changes in the pressure profile of cellular membranes and transduces the mechanical energy into electrical and/or chemical signals. MscL can be activated using ultrasonic or chemical activation methods to improve the absorp...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022001787 |
| _version_ | 1797978234776715264 |
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| author | Kalyan Immadisetty Adithya Polasa Reid Shelton Mahmoud Moradi |
| author_facet | Kalyan Immadisetty Adithya Polasa Reid Shelton Mahmoud Moradi |
| author_sort | Kalyan Immadisetty |
| collection | DOAJ |
| description | Mechanosensitive channel of large conductance (MscL) detects and responds to changes in the pressure profile of cellular membranes and transduces the mechanical energy into electrical and/or chemical signals. MscL can be activated using ultrasonic or chemical activation methods to improve the absorption of medicines and bioactive compounds into cells. However, re-engineering chemical signals such as pH change can trigger channel activation in MscL. This study elucidates the activation mechanism of an engineered MscL at an atomic level through a combination of equilibrium and non-equilibrium (NE) molecular dynamics (MD) simulations. Comparing the wild-type (WT) and engineered MscLactivation processes suggests that the two systems are likely associated with different active states and different transition pathways. These findings indicate that (1) periplasmic loops play a key role in the activation process of MscL, (2) the loss of various backbone-backbone hydrogen bonds and salt bridge interactions in the engineered MscLchannel causes the spontaneous opening of the channel, and (3) the most significant interactions lost during the activation process are between the transmembrane helices 1 and 2 in engineered MscLchannel. The orientation-based biasing approach for producing and optimizing an open MscL model used in this work is a promising way to characterize unknown protein functional states and investigate the activation processes in ion channels and transmembrane proteins in general. This work paves the way for a computational framework for engineering more efficient pH-sensing mechanosensitive channels. |
| first_indexed | 2024-04-11T05:19:45Z |
| format | Article |
| id | doaj.art-a4313cbf08634d1f9b9e32f56500c696 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:19:45Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-a4313cbf08634d1f9b9e32f56500c6962022-12-24T04:52:28ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012025392550Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channelKalyan Immadisetty0Adithya Polasa1Reid Shelton2Mahmoud Moradi3Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States; Corresponding author.Mechanosensitive channel of large conductance (MscL) detects and responds to changes in the pressure profile of cellular membranes and transduces the mechanical energy into electrical and/or chemical signals. MscL can be activated using ultrasonic or chemical activation methods to improve the absorption of medicines and bioactive compounds into cells. However, re-engineering chemical signals such as pH change can trigger channel activation in MscL. This study elucidates the activation mechanism of an engineered MscL at an atomic level through a combination of equilibrium and non-equilibrium (NE) molecular dynamics (MD) simulations. Comparing the wild-type (WT) and engineered MscLactivation processes suggests that the two systems are likely associated with different active states and different transition pathways. These findings indicate that (1) periplasmic loops play a key role in the activation process of MscL, (2) the loss of various backbone-backbone hydrogen bonds and salt bridge interactions in the engineered MscLchannel causes the spontaneous opening of the channel, and (3) the most significant interactions lost during the activation process are between the transmembrane helices 1 and 2 in engineered MscLchannel. The orientation-based biasing approach for producing and optimizing an open MscL model used in this work is a promising way to characterize unknown protein functional states and investigate the activation processes in ion channels and transmembrane proteins in general. This work paves the way for a computational framework for engineering more efficient pH-sensing mechanosensitive channels.http://www.sciencedirect.com/science/article/pii/S2001037022001787MscLMolecular dynamicsNon-equilibrium |
| spellingShingle | Kalyan Immadisetty Adithya Polasa Reid Shelton Mahmoud Moradi Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel Computational and Structural Biotechnology Journal MscL Molecular dynamics Non-equilibrium |
| title | Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| title_full | Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| title_fullStr | Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| title_full_unstemmed | Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| title_short | Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| title_sort | elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel |
| topic | MscL Molecular dynamics Non-equilibrium |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022001787 |
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