How Zn²⁺ ions affect the structure of the neurokinin A (NKA), neurokinin B (NKB) and substance P (SP)?

Neurokinin A (NKA), Neurokinin B (NKB) and Substance P (SP) are the most familiar neuropeptides which are part of large class of molecules that play important biological functions in the brain. Zinc is known to be released from neurons during neuronal activity. It is hypothesized that these neuropeptides have the ability to bind Zn²⁺ ions. In the current study, we examine the Zn²⁺-binding sites in NKA, NKB and SP and the effect of Zn²⁺ ions on their structures.

Our simulations show that in absence of Zn²⁺ ions, NKA has 2 main conformations: helical (Figure 1a) and random coil conformations. The experiments show that NKA is a random coiled. In presence of Zn²⁺ ions, both the simulations and the experiment illustrate that NKA show equilibration between α-helix (Figure 1b) and random coiled conformations.

Interestingly, in absence of Zn²⁺ ions, NKB has slightly helical structure and SP is a random coiled, but in presence of Zn²⁺ ions, NKB and SP are random coiled. These two peptides conserve the Zn²⁺-binding site (In NKB: Asp1, Asp4, and in SP: Two O atoms in the carboxylic group of the C-terminal). But, the Zn²⁺ ion in NKA is hopping between His1 and Asp4 (which is the preferred binding site) to the two O atoms in the carboxylic group of C-terminal. Therefore, we propose that NKB and SP can serve as excellent Zn²⁺ chelators for inhibition of amyloid aggregation.

Figure 1: Representative structural models of NKA (sequence: HKTDSFVGLM) in (a) absence of Zn²⁺ and (b) in presence of Zn²⁺.