Multiscale Simulations to Discover Self-Assembled Oligopeptides: A Benchmarking Study.

Peptide self-assembly is critical for biomedical and material discovery and production. While it is costly to experimentally test every possible peptide design, computational assessment provides an affordable solution to evaluate many designs and prioritize synthesis and characterization. Following a theoretical investigation, we present a systematic analysis of all-atom and coarse-grained simulations to predict peptide self-assembly. Benchmarking studies of two model dipeptides allow us to assess the impacts of intrinsic properties (such as amino acids and terminal modifications) and external environment (such as salinity) on the simulated aggregation. Further examination of 20 oligopeptides containing two to five amino acids shows good agreement among our theory, simulations, and prior experimental observations. The success rate of our prediction is 90%. Therefore, our theory, simulation, and analysis can be useful to identify peptide designs that can self-assemble and predict the potential nanostructures. These findings lay the ground for future virtual screening of peptide-assembled nanostructures and computer-aided biologics design.

Two-Dimensional Supramolecular Polymerization of DNA Amphiphiles is Driven by Sequence-Dependent DNA-Chromophore Interactions.

Two-dimensional (2D) assemblies of water-soluble block copolymers have been limited by a dearth of systematic studies that relate polymer structure to pathway mechanism and supramolecular morphology. Here, we employ sequence-defined triblock DNA amphiphiles for the supramolecular polymerization of free-standing DNA nanosheets in water. Our systematic modulation of amphiphile sequence shows the alkyl chain core forming a cell membrane-like structure and the distal π-stacking chromophore block folding back to interact with the hydrophilic DNA block on the nanosheet surface. This interaction is crucial to sheet formation, marked by a chiral "signature", and sensitive to DNA sequence, where nanosheets form with a mixed sequence, but not with a homogeneous poly(thymine) sequence. This work opens the possibility of forming well-ordered, bilayer-like assemblies using a single DNA amphiphile for applications in cell sensing, nucleic acid therapeutic delivery and enzyme arrays.

A Photoresponsive Intramolecular Triplex Motif That Enables Rapid and Reversible Control of Aptamer Binding Activity.

DNA switches that can change conformation in response to certain wavelengths of light could enable rapid and noninvasive control of chemical processes for a wide range of applications. However, most current photoresponsive DNA switches are limited by either irreversible switching or reversible switching with impractically slow kinetics. Here, we report the design of an intramolecular triplex photoswitch (TPS) design based on single-stranded DNA that undergoes rapid and reversible photoswitching between folded and unfolded states through isomerization of internal azobenzene modifications. After optimizing the performance of our photoswitch design, we used molecular dynamics simulations to reveal how individual azobenzenes contribute to the stabilization or destabilization of the triplex depending on their photoisomerization state. By coupling our TPS to an existing aptamer, we can reversibly modulate its binding affinity with less than 15 s of UV light exposure. We further demonstrate reproducible shifting in affinity over multiple cycles of UV and blue light irradiation without substantial photobleaching.