This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, PP1, in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. Protein functions in a living cell could be examined using atomistic MD simulations with realistic cellular environments.
Keywords
Inhibitor Binding, Atomistic Molecular Dynamics, Crowded Cellular Environment
Figure 1
Figure 2
Figure 3
Figure 4
This preprint is available for download as a PDF.
There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
- MovieS1.mov
Supplementary Movie 1: A canonical binding event observed in the dilute solution (D-7A*)
- MovieS2.mov
Supplementary Movie 2: A canonical binding event observed in Src8BSA solution (C8-7A*)
- SINatComm20200904.docx
Supplementary Information
Loading...
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Learn more about our company.
This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, PP1, in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. Protein functions in a living cell could be examined using atomistic MD simulations with realistic cellular environments.
Figure 1
Figure 2
Figure 3
Figure 4
This preprint is available for download as a PDF.
There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
- MovieS1.mov
Supplementary Movie 1: A canonical binding event observed in the dilute solution (D-7A*)
- MovieS2.mov
Supplementary Movie 2: A canonical binding event observed in Src8BSA solution (C8-7A*)
- SINatComm20200904.docx
Supplementary Information
Loading...