# Elucidating β‑Sheet Ordering in Lipopeptides Bearing Lysine-Rich Tripeptide Sequences: Fibrils versus Nanotapes

## TL;DR

This study explores how small changes in lipopeptide sequences affect their self-assembly into different nanostructures like fibrils or nanotapes in water.

## Contribution

The paper introduces a combined theoretical and simulation approach to explain sequence- and pH-dependent nanostructure formation in lipopeptides.

## Key findings

- C16-XKK lipopeptides form fibrils at high pH, while C16-KXK form stable lamellar nanotapes across a wide pH range.
- Molecular dynamics simulations show that β-sheet conformation is more favored in C16-XKK lipopeptides.
- Tyrosine-containing molecules exhibit higher hydrogen bonding compared to tryptophan-based ones.

## Abstract

The self-assembly in aqueous solution and conformation
of lipopeptides
C16-WKK, C16-KWK, C16-YKK and C16-KYK is compared and examined. Remarkable differences are
observed among the systems despite the small sequence changes comparing
C16-XKK with the C16-KXK homologue (X = W or
Y), depending on pH. These are rationalized using a molecular theory
for amphiphile self-assembly (MOLT) to predict the morphology along
with atomistic molecular dynamics simulations to probe local conformation
and packing, along with new experimental data from small-angle X-ray
scattering (SAXS) and FTIR spectroscopy. MOLT correctly describes
the high-pH morphology behavior, i.e., fibrils for C16-XKK,
and lamellar nanotapes for C16-KXK, although it predicts
micelles for all systems at low pH, whereas experiments indicate that
this only occurs for the C16-XKK lipopeptides, not the
C16-KXK, which form lamellar nanotapes stable over an extended
range of pH 2–12. Atomistic MD reveals β-sheet conformation
is more favored for the C16-XKK lipopeptides which also
have enhanced aggregation propensity compared to C16-KXK
analogues. The extent of π-stacking was higher for the latter
lamellar nanotape structures. The extent of hydrogen bonding is higher
for the tyrosine-containing molecules than the tryptophan-based ones.
The combination of a molecular theory and atomistic MD provides a
comprehensive insight into the remarkable sequence- and pH-dependent
molecular ordering within these model lipopeptides which will enable
the rational design of future peptide amphiphiles with targeted nanostructures
for desired applications.