Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 125, Issue 33, Pages 9547-9556Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.1c04052
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Funding
- NIH [GM 59796]
- Welch Grant [F-1896]
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The binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the ion channel transient receptor potential vanilloid 5 (TRPV5) is critical for its function, with atomically detailed simulations and the milestoning theory used to compute the free energy profile and kinetics. The protonation state of PIP2 and the influential channel residues were identified, with the switch between protonation states modeled as a diabatic transition halfway through the reaction.
The binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the ion channel transient receptor potential vanilloid 5 (TRPV5) is critical for its function. We use atomically detailed simulations and the milestoning theory to compute the free energy profile and the kinetics of PIP2 binding to TRPV5. We estimate the rate of binding and the impact of the protonation state on the process. Several channel residues are identified as influential in the association event and will be interesting targets for mutation analysis. Our simulations reveal that PIP2 binds to TRPV5 in an unprotonated state and is protonated in the membrane. The switch between the protonation state of PIP2 is modeled as a diabatic transition and occurs about halfway through the reaction.
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