Modeling and Simulations of Peptoids

Polypeptoids, or poly-N-substituted glycines, are a class of sequence defined polymers that are structural mimics of polypeptides. Polypeptoids currently have received a growing interest due to their improved thermal stability, larger chemical diversity, and easier synthetic pathways as compared to peptides. Their lack of backbone hydrogen bonding and stereochemistry coupled with their easily tunability make them an ideal prototypical model system to study the effect of secondary/non-covalent interactions on self-assembly in solution. In order to develop a molecular level understanding of the effect of secondary interactions on polypeptoid self-assembly, systematic studies were carried out using molecular dynamics simulations on several polypeptoid solutions. Firstly, atomistic molecular dynamics simulations were performed to study self-aggregation of a cyclic polypeptoid and its linear analog in a low dielectric solvent, namely methanol. The cyclic polypeptoids bearing zwitterionic end-groups showed small cluster formation experimentally, ranging from a single polypeptoid chain to small oligomers in methanol solution, while the experiments showed no aggregation in the linear case. Atomistic molecular simulation results revealed that the aggregation in the cyclic case was as results of several different interactions. During the initial approach of the two cyclic polypeptoids, the attractive dipole-dipole interaction dominates. At closer distance, the attractive solvophobic effect takes over, while the effective repulsive interaction resulting from solvation of the dipoles dramatically reduces the attractive dipole-dipole component. A second set of studies was carried out to investigate the micelle formation of sequence-defined singly charged ionic peptoid block copolymers consisting of a hydrophobic and a hydrophilic segment in aqueous solution. Results from this study demonstrated that water molecules mediate the structure and shape of micelles by interacting with the polymer chains and ionic monomers on the backbone. Specifically, a key interaction is that of the charged moiety with water that results in the charged group exposed to the solvent, even when it is placed next to the hydrophobic segment of the polypeptoid chain. This study contributed to our understanding of structure-property relationships in peptoid based soft matter systems. Finally, a coarse-grained (CG) model of N, N-dimethylacetamide, the backbone of the polypeptoid system, has been developed that can reproduce the solvation environment around the DMA molecule, as observed from the reference all-atom simulations. These results suggest a promising approach to develop CG models of complex peptoid with various side chains that will enable better sampling and longer simulation length scales