Biophysical and Computational Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, Karnataka, India.
J Chem Phys. 2024 Oct 28;161(16). doi: 10.1063/5.0226869.
Using a well-developed reaction coordinate in umbrella sampling, we studied the single peptide permeation through a model cancerous cell membrane, varying the hydrophilicity and the charge of the peptides. Two peptides, melittin and pHD108, were studied. The permeation mechanism differs from a barrel-stave-like mechanism to toroidal pore and vesicle formation based on the number and the placement of the hydrophilic amino acids in the peptide. Membrane curvature changes dynamically as the permeation process occurs. In the case of vesicles, the peptide traverses along a smooth, homogenous pathway, whereas a rugged, steep pathway was found when lipid molecules did not line up along the wall of the membrane (barrel-stave-like mechanism). A mechanism similar to a toroidal pore consists of multiple minima. Higher free energy was found for the permeating terminal containing charged amino acid residues. Vesicle formation was found for pHD108 peptide N-terminal with a maximum membrane thinning effect of 54.4% with free energy cost of 8.20 ± 0.10 kcal mol-1 and pore radius of 2.33 ± 0.07 nm. Insights gained from this study can help to build synthetic peptides for drug delivery.
利用伞状采样中开发良好的反应坐标，我们研究了单一肽通过模型癌细胞膜的渗透，改变肽的亲水性和电荷。研究了两种肽，即蜂毒素和 pHD108。渗透机制基于肽中亲水氨基酸的数量和位置从桶状样机制转变为环形孔和囊泡形成。随着渗透过程的发生，膜曲率动态变化。在囊泡的情况下，肽沿着光滑、均匀的途径穿过，而当脂质分子没有沿膜壁排列时（桶状样机制），则发现了崎岖、陡峭的途径。类似于环形孔的机制由多个最小值组成。含有带电荷氨基酸残基的渗透末端的自由能更高。发现 pHD108 肽 N 末端形成囊泡，最大膜变薄效应为 54.4%，自由能成本为 8.20 ± 0.10 kcal mol-1，孔径为 2.33 ± 0.07 nm。从这项研究中获得的见解可以帮助构建用于药物输送的合成肽。
