环肽因其在序列和成环方式上的多样性，显示出丰富的结构多样性与功能多样性，在生化研究中扮演越来越重要的角色，如自组装形成纳米管结构、与靶点蛋白结合参与代谢调控等。本论文以分子动力学模拟为主要手段，在微观至介观尺度上对特定类型环肽与小分子、磷脂膜和蛋白质等物质之间的相互作用进行了理论研究。具有左/右旋交替残基序列的首尾环肽可形成平环构象，平环间可反平行上下堆叠组装成纳米管结构，纳米管空腔可用于递送货物分子。采用Amber全原子力场对c[-(Aa)5-]自组装环肽纳米管结构进行模拟，结果表明c[-(Aa)5-]反平行二聚体、八聚体和无限长纳米管在298 K常温和373 K高温条件下均未发生解聚。反平行β-折叠片之间的单个氢键处于动态的生成和湮灭过程，但瞬时氢键总数足够维持纳米管结构不被破坏。通过伞状取样模拟绘制四甲基铵、胆碱和乙酰胆碱从外部水环境进入c[-(Aa)5-]反平行八聚体中心的平均力势曲线，结果显示三者进入过程的势能均呈在波动中下降的趋势，说明自组装环肽纳米管理论上具备递送此三种货物分子的能力。自组装环肽纳米管递送乙酰胆碱可成为治疗阿尔茨海默症的潜在方案。然而，具有疏水侧链的自组装环肽纳米管才能形成稳定跨膜通道，为揭示疏水型纳米管跨膜机制，采用Martini粗粒化力场系统考察了单体到八聚体聚合度下的c[-(Wl)4-]和c[-(Ql)4-]自组装环肽纳米管与DPPC甘油磷脂双分子层相互作用形成跨膜通道的能力，结果显示c[-(Wl)4-]纳米管与DPPC脂双层接触后会首先水平浸没入脂双层，然后通过调整倾角来自发形成跨膜纳米管通道，四聚体是c[-(Wl)4-]形成跨膜纳米管通道的临界聚合度；c[-(Ql)4-]纳米管在所有聚合度下均无法形成横跨DPPC脂双层的通道结构。伞状取样模拟显示提升聚合度导致c[-(Wl)4-]纳米管跨膜过程势能降低；导致c[-(Ql)4-]纳米管跨膜过程势能升高。c[-(Wl)4-]纳米管形成跨膜通道后，纳米管周边的DPPC分子会进行调整与纳米管结构相互契合，从而维持跨膜通道结构的稳定性。此部分研究为设计新型跨膜纳米管通道提供了理论依据。两亲型自组装环肽纳米管可通过毯式模型作用机制对细菌细胞膜和动物细胞膜表现出选择破坏性，推测其选择性与细胞膜特征参数相关。为验证上述推测，构建包括DPPE/DPPG、POPE/POPG、DOPE/DOPG和DPPC/DPPG、POPC/POPG、DOPC/DOPG在内的一系列Martini粗粒化二元混合脂双层并进行NPγT平衡模拟，系统考察了疏水尾端、极性头端和表面张力对二元混合脂双层的平衡特征参数所带来的影响。结果显示同等疏水尾端和极性头端条件下，表面张力越大脂双层越薄；同等表面张力和极性头端条件下，脂双层厚度按DPPX > POPX > DOPX顺序递减；同等表面张力和疏水尾端条件下，脂双层厚度按照PE > PG > PC顺序递减。对所有类型脂双层进行汇总分析显示脂双层厚度、平面密度和有序度三个特征参数呈正相关性，其中脂双层厚度与平面密度呈线性关系。c[-(Kl)4-]不会导致脂双层破裂， c[-(Wl)2-(Wr)-(Rk)-]破裂脂双层的临界时间期望值与脂双层平面密度呈指数关系。此部分研究为评估自组装环肽抗生素选择性提供了定性指标。西仑吉肽是典型环肽药物，其研发过程非常具有指导意义。为建立研发环肽药物的通用分子对接与虚拟筛选方法，以Amber全原子力场模拟获取西仑吉肽骨架构象空间，并开展骨架构象空间与受体整合素αvβ3的分子对接，经虚拟筛选后得到了与西仑吉肽晶体构象接近的对接构象，验证了从分子动力学模拟获取环肽骨架构象空间并将之用于分子对接的可行性。以另一种II型糖尿病靶点蛋白二肽基肽酶-IV为测试对象，以直链三肽和四肽库APX/APXX为配体进行初次对接和虚拟筛选，得到19条对二肽基肽酶-IV具有潜在抑制性的直链肽三肽和四肽序列。基于此19条直链三肽和四肽构建序列为CPXGGGGC和CPXXGGGC的二硫键环肽，并经分子动力学模拟获取其各自骨架构象空间。对19条二硫键环肽的骨架构象空间进行二次分子对接和虚拟筛选，得到对二肽基肽酶-IV的IC50值为256 μM的二硫键环肽序列CPWGGGGC。此部分研究建立了环肽药物的理论设计方法。;Cyclic peptides exhibit structural and functional diversity originated from their sequence and cyclization form variety, and thus are playing more and more important roles in biochemical research, i.e. self-assembling into nanotube structures, modulating metabolic pathways through binding to target proteins, etc. Using molecular dynamics simulation as the main research method, this study investigated the mutual interactions between certain kinds of cyclic peptides and other types of materials, such as small molecules, lipid membranes and proteins, from a microscopic or mesoscopic perspective of view.The cyclic peptides with L/D-alternating residues could adopt flat-ring shaped conformation. The nanotubes antiparallely assembled by flat-rings possess a hollow tubular structure, which could be used to deliver cargo molecules. The nanotubes assembled by c[-(Aa)5-] were simulated using the Amber all atom forcefield. The c[-(Aa)5-] dimer, octamer and infinite nanotube can all maintain structural stability at both 298 K and 373 K. A certain single hydrogen bond between the antiparallel β-sheet would experience dynamic creation and destruction; but the instantaneous total hydrogen bond counts are abundant enough to maintain the tubular structure. The energy profiles describing tetramethylammonium, choline and acetylcholine entering the c[-(Aa)5-] octamer center from the bulk water were separately drawn using umbrella sampling molecular dynamics simulation. All three profiles exhibit fluctuation potential drop, indicating that peptide nanotubes are capable of delivering these cargo molecules. The delivery of acetylcholine by self assembling cyclic peptides provides a potent method for the treatment of Alzheimer's disease.However, only those nanotubes contain hydrophobic sidechains could form transmembrane pore structures.The transmembrane pore forming capabilities of c[-(Wl)4-] and c[-(Ql)4-] oligomers, from monomer to octamer, on the DPPC glycerol phospholipid bilayer were investigated using the Martini coarse grained forcefield. The c[-(Wl)4-] oligomers are capable of forming pore structures by horizontally submerging into the membrane and adjusting their tilt angles, but such phenomenon can only be observed for tetramer and above oligomeric states. The c[-(Ql)4-] oligomers can not form transmembrane pore structures regardless of their oligomeric states. Umbrella sampling simulation reveal that elevation of the oligomeric state would lower the transmembrane potential energy of c[-(Wl)4-] whereas increase that of c[-(Ql)4-]. Once the transmembrane pore structures are formed, peripheral DPPC molecules would take adjustment to be compatible with the c[-(Wl)4-] oligomers. This part of study shed light on the design of noval transmebrane nanotubes.Amphiphilic self-assembling cyclic peptide nanotubes could selectively disrupt bacterial membrane rather than mammalian cell membrane. Such selectivity is assumbed to be related with intrinsic properties of membranes. To verify such hypothesis, a series of Martini coarse grained binary mixed bilayers were built and equilibrated, including DPPE/DPPG, POPE/POPG, DOPE/DOPG and DPPC/DPPG, POPC/POPG, DOPC/DOPG. Elevating the surface tension exerted on the membrane would lead to membrane thinning; the membrane thickness would decrease in the order of DPPX > POPX > DOPX given same surface tension and polar head conditions; and the membrane thickness would decrease in the order of PE > PG > PC given same surface tension and aliphatic tail conditions. The membrane thickness, planar density and ordering state are positively related, especially that the membrane planar density and thickness are in linear relationship. c[-(Kl)4-] does not lead to disruption of lipid bilayers; the time needed to disrupt the membrane by c[-(Wl)2-(Wr)-(Rk)-] is expected to grow exponentially with the increase of the planar density. This part of study provides qualitative standard for the validation of antimicrobial self-assembling cyclic peptides.As a typical cyclic peptide pharmaceutical, cilengitide provides helpful guidance for the development of same type of peptide drugs. To build the general methodology of cyclic peptide molecular docking and virtual screening, the backbone conformational space of cilengitide, obtained through molecular dynamics simulation under Amber all atom forcefield, was docked with the integrin receptor αvβ3 and a backbone conformation similar to that of the reported crystal conformation was virtually screened, thus verifying the methodology of cyclic peptide docking using backbone conformational space. 19 potent inhibitory linear tri- or tetra-peptide sequences against dipeptidyl peptidase-IV were obtained through molecular docking and virtual screening on the linear peptide libraries APX/APXX. These 19 linear peptides were subsequently disulfide cyclized in the form of CPXGGGGC / CPXXGGGC. Secondary molecular docking and virtual screening on the backbone conformational spaces of these disulfide cyclic peptides were carried out, and an inhibitory sequence CPWGGGGC with an IC50 256 μM was obtained. This part of study established the theoretical designing method of cyclic peptide drugs.