Molecular Dynamics Simulation Study Of Functional Cyclic Peptides

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?-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[-(Q1)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?v?3 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 ?M was obtained.This part of study established the theoretical designing method of cyclic peptide drugs.