The Effect Of Molecular Structures And Microscopic Interactions On Peptides Self-assembly

Due to the excellent performance of self-assembly,the design and manufacture of self-assembled peptides nanomaterials become a hot research field in the development of novel nanomaterials and biomaterials.Peptide,consisting of amino acid residues,is usually looked as hydrolyzed protein.Therefore,peptide molecules generally have some amazing features such as adjustable composition and sequence,biodegradable,biological compatibility and biological activity.Peptide is shorter than protein and has a simple molecular structure,but is able to form richful hierarchical morphology by self-assembling.In this thesis,we study the relationship between peptide molecular structure and their self-assembling nanostructure,using a combination of experimental characterization and molecular simulation.Meanwhile,we investigate the micro interactions during self-assembling and the effect of their competitions on the peptide self-assembling nanostructures.To understand how molecular interactions lead to the self-assembly of twisted,helical and flat nanoribbons,we have compared the hierarchical self-assembly processes of three selected octapeptides with the same amino acid composition but different sequences by both experiments and molecular dynamics（MD）simulations.KE-F8（NH₂-KEFFFFKE-CONH₂）and EK-F8（NH₂-KEFFFFEK-CONH₂）have the same distribution of hydrophobic residues and only differ by swapping the positive and negative charged residues at their C-terminals,while KFE-8（NH2-KFEFKFEF-CONH₂）differs from KE-F8 and EK-F8 by having all hydrophobic and charged residues evenly distribued.MD simulations indicated that the competition between electrostatic and hydrophobic interactions at the molecular level results in different initial packing modes:KE-F8 monomers form completely matched anti-parallelβ-sheets,EK-F8 monomers align with one residue shifting,and KFE-8 monomers packβ-sheets with two heterogeneous surfaces,consistent with previously suggested models.Driven by inter-strand and inter-sheet interactions,further growth of these molecular templates leads to larger oligomers with different twisting and stacking degrees,which are structurally consistent with the experimentally observed self-assembled morphologies.Further MD simulations showed that the competition between intra-β-sheet and inter-β-sheet interactions is responsible for the different twisting and stacking degrees ofβ-sheets and the subsequent formation of different nanostructures（twisted ribbons for KE-F8,helical ribbons/tubes for EK-F8 and flat ribbons for KFE-8）.This study thus provided an important mechanistic insight into the fine tuning of molecular packing and interactions via peptide sequence variation leading to controllable self-assembly of twisted,helical and flat nanostructures.In order to study how the conformational propensity of individual amino acid residue,primary structures（i.e.,adjacent residues and molecular lengths）,and intermolecular interactions affect the self-assembling properties of peptides,we report the use of replica exchange molecular dynamics（REMD）to investigate the monomers,dimers and trimers of a series of short surfactant-like peptides（I₃K,L₃K,L₄K and L₅K）,in which the hydrophobic residues are an pair of isomers（Isoluecine（Ile,I）and leucine（Leu,L））.For 4-residue peptides X₃K（I₃K and L₃K）,the results show that their different aggregating behaviors arise from the intrinsic conformational propensities of isoleucine and leucine.For L_mK peptides（L₃K,L₄K and L₅K）,the molecular length is found to dictate their aggregation via primarily modulating intermolecular interactions.Increasing the hydrophobic length of L_mK peptides enhances their intermolecular H-bonding and promotes the formation ofβ-strands in dimer and trimer aggregates,making the intrinsic preference of Leu for helical structures overwhelmed.Thus,the interplay between the conformational propensity of individual amino acid residues for secondary structures and molecular interactions determines the self-assembling properties of the peptides,and the competition between intramolecular and intermolecular H-bonding interactions determines the probability ofβ-sheet alignment of peptide molecules.These results are validated by comparing simulated and experimental CD spectra of the peptides.This study is expected to be helpful in designing self-assembling short peptides and mechanistically understanding their self-assembly behaviors.Following the above research,we found that each amino acid has its specific inherent conformational propensity which play an important influence on the peptide molecular self-assembly.We try to make use of this property of amino acids in designing new peptide moleucles.Because the enantiomeric amino acid residue have conformational propensity of opposite optical handedness,as L-type leucine（L-Leu）has strong propensity to form right-handedα-helix conformation（α_R）,it is predictable that D-type leucine（D-Leu）has strong propensity to form left-handedα-helix（α_L）conformation.Therefore,the properties of L-Leu and D-Leu could be applied to build a new surfant-like peptides based onα-sheet secondary structure.Compared with L₄K,L^DLL^DLK monomer has a strong ability to form extended backbone.We then studied the intermolecular packing modes of L₄K and L^DLL^DLK in dimer and trimer using REMD.The result shown that both of L₄K and L^DLL^DLK could form parallel,anit-parallel and parallel/anit-parallel mixed packing modes.However,in theα-sheet packing modes of L^DLL^DLK,α-strands are free to slip with each other,maintaining a sufficient number of intermolecular hydrogen bonds to stabilize the inter-α-strand arrangements meanwhile.Therefore,it is hypothesized that the extended molecular backbone as well as the flexible and stable intermolecular packing lead to the differernt self-assembled nanostructures,i.e.L^DLL^DLK form into nanotubes while L₄K with the opposite properites form into nanofibers.In a summary,we studied the effect of different amino acid sequences with the same amino acid residue composition,as well as different isomeric residues and enantiomeric residues in the same position of sequence on the self assembling nanostructures.Using molecular dynamics simulation results we analyzed the micro interactions in the self-assembled nanostructure,revealing the relationship between the competition of micro interactions and the self-assembling of peptides.