1. Structure-based rational design of self-inhibitory peptides to disrupt the intermolecular interaction between the troponin subunits C and I in neuropathic pain.
- Author
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Yu, Junmin, Wang, Shilei, Yu, Junjie, Liu, Chuansheng, Xu, Fenghe, Wang, Shijie, Yi, Yusheng, and Yin, Yanwei
- Subjects
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INTERMOLECULAR interactions , *TROPONIN , *NEUROPATHY , *MOLECULAR dynamics , *C-terminal residues - Abstract
The troponin (Tn) is a ternary complex consisting of three subunits TnC, TnI and TnT; molecular disruption of the Tn complex has been recognized as an attractive strategy against neuropathic pain. Here, a self-inhibitory peptide is stripped from the switch region of TnI interaction interface with TnC, which is considered as a lead molecular entity and then used to generate potential peptide disruptors of TnC–TnI interaction based on a rational molecular design protocol. The region is a helical peptide segment capped by N- and C-terminal disorders. Molecular dynamics simulation and binding free energy analysis suggests that the switch peptide can interact with TnC in a structurally and energetically independent manner. Terminal truncation of the peptide results in a number of potent TnC binders with considerably simplified structure and moderately decreased activity relative to the native switch. We also employ fluorescence polarization assays to substantiate the computational findings; it is found that the rationally designed peptides exhibit moderate or high affinity to TnC with dissociation constants K D at micromolar level. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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