Structural Insights and Influence of Terahertz Waves in Midinfrared Region on Kv1.2 Channel Selectivity Filter

Abstract

Potassium ion channels are the structural basis for excitation transmission, heartbeat, and other biological processes. The selectivity filter is a critical structural component of potassium ion channels, whose structure is crucial to realizing their function. As biomolecules vibrate and rotate at frequencies in the terahertz band, potassium ion channels are sensitive to terahertz waves. Therefore, it is worthwhile to investigate how the terahertz wave influences the selectivity filter of the potassium channels. In this study, we investigate the structure of the selectivity filter of Kv1.2 potassium ion channels using molecular dynamics simulations. The effect of an electric field on the channel has been examined at four different resonant frequencies of the carbonyl group in SF: 36.75 37.06, 37.68, and 38.2 THz. As indicated by the results, 376GLY appears to be the critical residue in the selectivity filter of the Kv1.2 channel. Its dihedral angle torsion is detrimental to the channel structural stability and the transmembrane movement of potassium ions. 36.75 THz is the resonance frequency of the carbonyl group of 376GLY. Among all four frequencies explored, the applied terahertz electric field of this frequency has the most significant impact on the channel structure, negatively impacting the channel stability and reducing the ion permeability by 20.2% compared to the absence of fields. In this study, we simulate that terahertz waves in the mid-infrared frequency region can significantly alter the structure and function of potassium ion channels and that the effects of terahertz waves differ greatly based on frequency.

Figure 1

Schematic diagram of the simulation model. (a) Pore domain of the Kv1.2 potassium channel and the initial potassium ion loading state in the selectivity filter (SF). For clarity, only two of the four protein subunits are shown in the New Cartoon. For the SF, the licorice modality is employed where S₀–S₄ and S_c represent six potassium ion sites. The six sites are composed of oxygen atoms O₁–O₆. O₁–O₅ are carbonyl oxygen atoms from the conserved sequence TVGYG in the potassium channel. O₆ is the oxygen atom for the threonine side chain at the SF entrance; (b) Bilayer model. VDW spheres are used to represent ions, with green spheres representing potassium ions and orange spheres representing chloride ions. Water molecules are represented by blue QuickSurf, while membrane molecules are represented by silver lines. The membrane divides the system into two layers: ComA and ComB. As shown in the figure, the dotted line represents the position of the channel protein’s center of mass.

Figure 2

Vibrational power spectra of the carbonyl group of the conserved residue TVGYG in SF. They correspond to the residue sequence numbers 374–378 in 3LUT, as shown in the figure. TVGY is the single-letter abbreviation for threonine, valine, glycine, and tyrosine, respectively.

Figure 3

Distribution of dihedral angles in SF. (a) Schematic structure of SF of Kv1.2, where the green balls represent the five sites S₀–S₄. Licorice denotes SF; the small green balls represent the carbonyl carbon atoms (C) or the side-chain carbon atoms (CB) of 374THR; the red balls represent the carbonyl oxygen atoms (O) or the hydroxyl oxygen atoms (OG1) of 374THR; the gray balls represent the α carbon atoms (CA); and the blue balls represent the amido nitrogen atoms (N). (b) Distribution probability of each dihedral angle in SF. (c) Probability of the number of N-CA-CB-OG1 dihedral angles of the 374THR side chain flipped in four chains. (d) Probability of the number of N–CA–C–O dihedral angles of 376GLY torsion in four chains. (e) Probability of the combined state of the N–CA–C–O dihedral angle of 375VAL in four chains.

Figure 4

Relationship between the dihedral angle states of 375VAL, 376GLY, and ion permeability events. md1–md6 denote six independent simulations. (a) Relationship between the 375VAL dihedral angle and ion permeation events. (b) Relationship between the 376GLY dihedral angle and ion permeability events.

Figure 5

Effect of 376GLY dihedral angle torsion on ion transmembrane motion. (a) Evolution of the 376GLY dihedral angle and ion flux over time. (b) Schematic diagram of 376GLY dihedral angle torsion. (c) Effect of 376GLY dihedral angle torsion on the distance between the 376GLY carbonyl oxygen atom O₃₇₆ and the potassium ion in the S₂ site. (d) Effect of 376GLY dihedral angle torsion on the Coulomb potential energy between O₃₇₆ and the potassium ion in the S₂ site. (e) Effect of 376GLY dihedral angle torsion on the distance between the carbonyl oxygen atom O₃₇₆ of 376GLY and the carbonyl oxygen atom of 377TYR.

Figure 6

Critical role of 376GLY in Kv1.2 potassium ion channels. (a) Effect of different numbers of 376GLY dihedral angle torsions in the four chains on the SF pore diameter. For each site, the pore diameter is measured as the distance between the α carbon atoms of the residues forming the site in the two chains opposite each other. The figure displays the changes in the aperture under different numbers of torsions compared to the untorsioned state, with the unit in Ångströms (Å). The pore diameters of the S₀–S₄ sites in the untorsioned state are 9.15, 8.3, 8.2, 8.1, and 8.8 Å, respectively. (b) Effect of different numbers of 376GLY dihedral angle torsions in the four chains on the lengths of each SF site. Site length is defined as the distance between the upper and lower oxygen atoms corresponding to the site. The figure displays the changes in site length under different numbers of torsions compared to the untorsioned state, with the unit in Ångströms (Å). The lengths of sites S₀–S₄ in the untorsioned state are 4.32, 3.6, 3.4, 3.6, and 3.3 Å, respectively. (c) Probability of each site in the SF being occupied by a potassium ion. (d) Retention time of potassium ions at each site. (e) RMSF values of α carbon atoms of residues at each site.

Figure 7

Effect of a terahertz electric field on the structure of the Kv1.2 potassium ion channel. (a) Kv1.2 potassium ion channel structure, with orange representing the outer helix, light purple representing the turret, gray representing the pore helix, yellow representing the selectivity filter, dark green representing the S6 loop, and blue representing the inner helix. It should be noted that the S4–S5 linker is included within the outer helix for convenience in our analysis. (b) Effect of terahertz fields on the structure of various regions of the channel. The height of the bars represents the average value of RMSD from six simulations, indicating the average extent of deviation of the channel structure from its initial state. The error bars on the bars illustrate the average standard deviation of the RMSD from six simulations, indicating the average fluctuation level of structures.

Figure 8

Effect of a terahertz electric field on the structure of the Kv1.2 selectivity filter. (a) Effect of terahertz electric fields on the ratio of dihedral angle anomalies at each site of the SF. (b) Effect of terahertz electric fields on the RMSF of each residue α carbon atom in SF. (c) Effect of terahertz electric fields on the SF aperture. For each site, the pore diameter is measured as the distance between the α carbon atoms of the residues forming the site in the two chains opposite each other. The figure illustrates changes in the average aperture when subjected to a terahertz electric field, in comparison to the scenario without an applied field. In the absence of an applied field, the average apertures at S₄–S₀ sites measure as follows: 9.1, 8.3, 8.1, 8.1, and 8.8 Å. (d) Effect of the terahertz electric fields on the length of SF sites. The figure illustrates changes in the average site length when subjected to a terahertz electric field in comparison with the scenario without an applied field. In the absence of an applied field, the average length of S₄–S₀ sites measured as follows: 3.3, 3.6, 3.3, 3.7, and 4.3 Å.

Figure 9

Terahertz electric field effects on potassium ion transmembrane movement. (a) Potassium ion occupancy probability at each site. (b) Water molecule occupancy probability at each site. (c) Probability of the simultaneous presence of two or three potassium ions in SF. (d) Ion flux within 2.4 μs.