Khurana Ekta, Nielsen Steven O, Ensing Bernd, Klein Michael L
Center for Molecular Modeling and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
J Phys Chem B. 2006 Sep 28;110(38):18965-72. doi: 10.1021/jp057471y.
The self-assembly of cyclic D,L-alpha-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-)4-]2 and cyclo [(-L-Trp-D-Leu-)4-]2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the phi and psi dihedral angles of a single uncapped ring in nonane lie in the beta-sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.
环状D，L-α-肽自组装成中空纳米管是其作为抗菌和药物递送剂应用中的关键机制步骤。为了理解这一过程，对由环[(-L-Trp-D-N-MeLeu-)4-]2和环[(-L-Trp-D-Leu-)4-]2亚基形成的环状肽二聚体在非极性（壬烷）和极性（水）溶剂中进行了分子动力学（MD）模拟。在MD轨迹的整个10 ns长度内，观察到二聚体仅在非极性溶剂中稳定。根据亚基间氢键、与溶剂的氢键以及环的平面性，对二聚体在不同溶剂中的行为进行了合理化解释。结果表明，壬烷中单个未封端环的φ和ψ二面角位于拉氏图的β-折叠区域，环保持扁平构象。基于雅尔津斯基等式进行了引导分子动力学（SMD）模拟，以获得作为壬烷中封端二聚体两个环之间距离函数的平均力势。还表明，由于肽环的两亲性，单个肽亚基更倾向于驻留在壬烷/水界面附近而不是本体溶剂中。目前的MD结果为使用MD模拟研究脂质双层中环状肽纳米管的形成机制奠定了基础。
