Simulation studies of the mechanism of translocation of cell penetrating peptides

描述（由申请人提供）：细胞穿透肽（CPP）是高阳离子，亲水，短，能够跨细胞膜转运的肽。这些多肽具有携带各种分子大小的货物的特殊性质，如蛋白质、核酸、肽核酸和其他生物和非生物分子。这些多肽作为一种将大分子输送到细胞中的治疗手段已被广泛研究。预计CPP技术的进一步发展和完善将提供药物传递载体、细胞成像技术和分子治疗。提出的研究的目的是建立一个原子水平的模型的机制和能量的转运这些肽跨越脂质双层。该模型将为进一步开发有效跨细胞膜转运的CPP序列提供基础。我们还将研究CPP肽的二级结构和序列对其与膜相互作用的影响。这些研究将帮助我们设计新的序列，这些序列将更有效地转运，因此需要更小剂量的CPPs。我们还假设一些阳离子抗菌肽（AMP），如蛋白-1，将通过一种与细胞穿透肽易位机制共享许多特征的机制插入脂质双分子层。我们将研究PG-1与模拟细菌和真核生物细胞膜的模型脂质双层的相互作用，以了解AMP对细菌细胞的选择性。我们的研究是基于广泛的分子动力学模拟和分子模型。我们的研究可能会导致更好的细胞穿透肽和新的抗菌肽的开发。

DESCRIPTION (provided by applicant): Cell penetrating peptides (CPP) are highly cationic, hydrophilic, short, peptides capable of translocating across the cell membrane. These peptides have the special property of carrying with them cargoes of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. It is anticipated that the further development and refinement of CPP techniques will provide drug delivery vectors, cellular imaging techniques, and molecular therapeutics. The objective of the proposed research is to develop an atomic level model of the mechanism and energy of translocation of these peptides across lipid bilayers. This model will provide the basis of further development of CPP sequences that effectively translocate across cell membranes. We will also study the effect secondary structure and sequence on the interaction of the CPP peptides with membranes. These studies will help us design new sequences that will translocate more efficiently, and will therefore require smaller dosage of CPPs. We also postulate that some cationic antimicrobial peptides (AMP), like protegin-1, will insert into the lipid bilayer by a mechanism that shares many features with the mechanism of translocation of cell penetrating peptides. We will study the interaction of PG-1 with model lipid bilayers that mimic bacterial and eukaryote cell membranes to understand the selectivity of AMP to bacterial cells. Our studies are based on extensive molecular dynamics simulations and molecular modeling. Our research may lead to the development of better cell penetrating peptides and new antimicrobial peptides. PUBLIC HEALTH RELEVANCE: Cell penetrating peptides have the special property of carrying with them cargos of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. This project aims at developing an atomic level description of the up to now elusive mechanism of translocation of these peptides across cells. The elucidation of this mechanism will enable the development of more efficient delivery vectors for imaging and therapeutic purposes.