Exploration of the Nucleation Pathway for Supramolecular Fibers

Abstract

The pathway for supramolecular fiber formation is coupled with the underlying order of the self-assembling molecules. Here, we report on atomistic molecular dynamics simulations to characterize the initial stages of the self-assembly of a model drug amphiphile in an aqueous solution. We perform two-dimensional metadynamics calculations to characterize the assembly space of this model drug amphiphile�Tubustecan, TT1. TT1 is composed of the hydrophobic anticancer drug, Camptothecin (CPT), conjugated to a hydrophilic polyethylene glycol (PEG) chain. We find that the aromatic stacking of CPT drives the formation of a higherdensity liquid droplet. This droplet elongates and can form a higher-ordered supramolecular assembly upon reorganizing and forming an interface and additional aromatic stacking of the drugs. We show that novel reaction coordinates tailored to this class of molecules are essential in capturing the underlying degree of molecular order upon assembly. This approach can be refined and extended to characterize the supramolecular assembly pathway of other molecules containing aromatic compounds.

Molecular Dynamics Simulations of Polyelectrolyte Complexes

“…However, theoretical tools, such as free energy methods, to characterize the underlying molecular pathway based on peptide chemistry can be further developed and refined. We are currently exploring the potential of advanced free energy methods in molecular dynamics such as metadynamics to describe fluctuations in peptide density and the formation of liquid droplets on the pathway to supramolecular fibers . Overall, the trends observed here suggest an opportunity to rationalize the behavior of charged peptides in the context of varying hydrophobicity from the sequence level up.…”

Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates

“…A continuing challenge in these materials comes in elucidating and controlling the contributions from prodrug–prodrug interactions in the desolvated nanofiber core to the self-assembly pathway and the material properties of the hydrogels. Molecular dynamics simulations have identified the directive forces of prodrug–prodrug interactions as dominant in the early assembly stages of sPDC and other amphiphilic prodrug systems. − Previous work has also demonstrated the complexity of navigating the sPDC free energy landscape as well as the drastic changes to the thermodynamics of assembly that result from small topological and chemical changes to the prodrug design . Furthermore, these model systems showed evidence of competitive organizing forces in the prodrug and β-sheet peptide domains, supporting contributions from prodrug modification to the energetics of self-assembly that can interfere with the intended directionality of the fused peptide …”

Engineering π-Conjugation of Phenylalanine Derivatives for Controllable Chiral Folding and Self-Assemblies

“…Supramolecular self-assembly of small molecules exhibits complex aggregation routes depending on the molecular geometry-directed arrangements that are affected by both thermodynamic and kinetic factors. − Investigating π–π staking interactions in the occurrence, transformation, inversion and amplification of chirality at supramolecular scale holds vital significance to fabricate chiroptical materials. − Small chiral compounds with two or multiple aromatic entities serve as effective building units for controlling supramolecular organization, attributed to the directional growth aided by aromatic forces . π–π staking interactions are well-known to play a vital role in the thermal stability and folding behavior which have been employed in tuning supramolecular chirality, structure and properties. − However, the influence of folding behavior on the self-assembly and chiral transfer processes is rarely addressed.…”