De Novo Design of Glycan Foldamers with Programmable Tertiary Structure

TL;DR

Scientists designed glycans that can form rigid 3D structures, showing glycans can be programmed for specific shapes and functions.

Contribution

First de novo design of glycans with programmable tertiary structures using first-principles and experimental validation.

Findings

A rigid trisaccharide turn unit directs backbone directionality into antiparallel geometry.

Combining the turn unit with cellulose-like strands forms stable sheet-like tertiary structures.

SAXS and NMR confirmed the designed glycans adopt rigid 3D conformations in solution.

Abstract

De novo molecular design has yielded proteins
and peptides with structures and functions beyond those found in nature.
Despite the potential for glycans to form a broader scope of well-defined
tertiary architectures, owing to the numerous conjugation sites and
stereocenters, no one has yet built glycans with targeted structures
and functions from scratch. Here, we designed glycan sequences that
fold into programmable 3D architectures. Starting from first-principles,
we create a linear glycan that spontaneously adopts a rigid tertiary
structure not reported for natural glycans. Considering stereochemical
and spatial orientation, we identify a rigid trisaccharide turn unit
that programs backbone directionality, driving folding into antiparallel
geometry. The combination of this turn unit with multiple cellulose-like
strands completes our design, stabilizing a tertiary sheet-like folding,
as confirmed by nuclear magnetic resonance spectroscopy and small-angle
X-ray scattering (SAXS). To quantitatively evaluate the conformational
landscape of our glycans in aqueous solution, we built a semiautomated
protocol that integrates SAXS data with molecular dynamics simulations,
demonstrating further the effectiveness of our design principles.
This is an important step to design and control conformation populations,
not just single structures in the solid state or of unknown prevalence
in the solution phase. Together, these results show that glycans can
be programmed to adopt rigid tertiary structures on demand, opening
new avenues for de novo glycan-based architectures
in synthetic glycobiology, catalysis, and materials science.

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