Thermal properties and non-bonded interactions in human PMP2 variants: A molecular dynamics study

Charcot-Marie-Tooth disease has been known for a long time, affecting population worldwide. Many studies on this disease have been conducted, including clinical as well as computational, but no effective medical cure has yet been found. This disease is caused due to mutation in the human peripheral myelin protein 2 (PMP2) responsible for myelin formation and maintenance. In this research work, we have done a comparative molecular dynamics study on the PMP2 protein and its M114T mutant variant, focusing on non-bonded interactions and thermal properties in a biologically relevant environment. The primary objective was to explore the structural differences between the two proteins at temperatures of 305 K, 310 K, and 315 K. Using the NAMD software for molecular dynamics simulations, various analyses were performed, including RMSD estimation, counting number of hydrogen bond formation, salt bridge occupancy assessment, estimation of vdW and electrostatic interaction energies in the system, and estimation of thermal diffusivity of the proteins as well as specific heat capacity (Cv) of the system. The results suggested slight difference between the structure of the two proteins. In the mutant, a slight increase in RMSD values was observed, suggesting a minor reduction in structural stability compared to the wild-type protein. The number of hydrogen bonds formed was generally higher in the wild-type protein, with slightly more differences observed at 305 K and 315 K than at 310 K. Analysis of salt bridge occupancy revealed notable differences in the formation patterns between the two proteins. The mutation was found to have a greater impact on salt bridge formation. In addition to this, the vdW and electrostatic interaction energies were found to be lower in the system with mutant variant, with both energies decreasing gradually as temperature increased, indicating a more robust interaction profile in the system with wild-type protein. Also, the estimated value of thermal diffusivity indicated that the mutant was slightly more efficient at conducting heat than the wild-type protein; the thermal diffusivity of both proteins was much lower than that of water. Finally, a non-linear (concave nature) change in Cv with temperature was observed in both protein systems. The work was further extended to verify the Maxwell-Boltzmann distribution law which confirmed the proper distribution of kinetic energy among particles, and the temperature fluctuation was found to follow a Gaussian distribution during the NVE simulation, which was as expected.