Protein tertiary packing is nearly achiral
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The chirality of proteins originates at the Cα stereocentre of each L-amino acid, and is expressed in secondary structure as the consistent twist of α-helices and β-sheets. How far does this handedness propagate as secondary-structure elements pack into a tertiary fold? This question is central to the development of neural networks for the design of heterochiral and mixed-chirality proteins containing mirror-image D-amino acids. Such networks are most effectively trained on the far more abundant structural data available for natural all-L proteins, yet in practice they must generate and evaluate the reflected, D-configured counterparts, which are not explicitly represented in the training set. Here, I develop a spatial tessellation-based parity-odd descriptor, the signed volume of Delaunay tetrahedra ( V D ), to measure how chirality is distributed in protein structure. Reflecting a structure only flips the sign of any parity-odd descriptor, so the asymmetry of the V D distribution quantifies the chirality of a given sequence-local or tertiary structural element. I find that the signed Delaunay volume distribution within individual secondary-structure elements is strongly asymmetric, but this handedness largely cancels once elements pack against one another. The resulting tertiary distribution is nearly symmetric across a broad range of structures, from monomers to protein-protein and protein-ligand complexes. Individual folds can nonetheless be strongly handed at the tertiary scale, solenoid and repeat proteins most of all, yet across a broad sample of the fold universe this handedness cancels, leaving the ensemble near-achiral. Tertiary packing is therefore only weakly chiral, with the small residual handedness greatest at binding interfaces and near-zero in the buried core. How much chirality a model perceives in a D-protein is thus largely a choice of representation, a trade-off between reflection symmetry and the richness of structural information the representation retains. Because V D reduces the parity-odd content of each structural element to a single scalar while capturing tertiary protein packing, it offers a natural representation for the design of heterochiral complexes and mixed-chirality proteins.
Significance Statement
The macromolecules of life are handed, and this mirror-asymmetry is built into every protein at the scale of its amino-acid monomers. Local segments of proteins are also strongly handed. Alpha helices and beta sheets are consistently right-handed. Does this handedness build up through the layers of a protein’s structure, as in some synthetic polymers, or cancel? Using a geometric test across thousands of structures, we find that it largely cancels: the 3D-packing of a folded protein, when described as a tetrahedral tessellation, is almost symmetric under reflection, though its building blocks are not. This means that the design of mirror-image D-protein binders, which are attractive as protease-resistant, low-immunogenicity drug candidates, could rely on AI models trained only on natural L-proteins, using representations developed here.
