The binding process of BmKTX and BmKTX-D33H toward to Kv1.3 channel: a molecular dynamics simulation study

Abstract

The potassium channel Kv1.3 is an important pharmacological target and the Kaliotoxin-type toxins (α-KTX-3 family) are its specific blockers. Here, we study the binding process of two kinds of Kaliotoxin-type toxins:BmKTX and its mutant (BmKTX-D33H) toward to Kv1.3 channel using MD simulation and umbrella sampling simulation, respectively. The calculated binding free energies are -27 kcal/mol and -34 kcal/mol for BmKTX and BmKTX-D33H, respectively, which are consistent with experimental results. The further analysis indicate that the characteristic of electrostatic potential of the α-KTX-3 have important effect on their binding modes with Kv1.3 channel; the residue 33 in BmKTX or BmKTX-D33H plays a key role in determine their binding orientations toward to Kv1.3 channel; when residue 33 (or 34) has negative electrostatic potential, the anti-parallel β-sheet domain of α-KTX-3 toxin peptide will keep away from the filter region of Kv1.3 channel, as BmKTX; when residue 33(or 34) has positive electrostatic potential, the anti-parallel β-sheet domain of α-KTX-3 toxin peptide will interact with the filter region of Kv1.3 channel, as BmKTX-D33H. Above all, electrostatic potential differences on toxin surfaces and correlations motions within the toxins will determine the toxin-potassium channel interaction model. In addition, the hydrogen bond interaction is the pivotal factor for the Kv1.3-Kaliotoxin association. Understanding the binding mechanism of toxin–potassium channel will facilitate the rational development of new toxin analogue.

Communicated by Ramaswamy H. Sarma

Keywords:

• MD simulation
• umbrella sampling simulation
• Kv1.3 channel
• α-KTX-3 toxin
• BmKTX
• BmKTX-D33H
• electrostatic potential
• hydrogen bond

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors thank the computational support by Laboratory of Theoretical and Computational Chemisty, This work was support in part by National Natural Science Foundation of China (NSFC) (21373099), (21573090), (81573063), Shanghai Municipal Health Commission (20194047), Youth cultivation fund of Beihua University (2017qnj105), Science and technology project of Jilin Provincial Department of Education (jjkh20180334kj).