Crystalline materials made from molecular components can possess useful properties that can be tailored through judicious selection of their molecular building blocks.The utility of these materials, however, depends on molecular packing in the crystal lattice as well as the properties of the individual molecules themselves. Consequently, further advances hinge on our ability to manipulate solid-state structure in a rational and systematic manner. Although computational prediction of crystal structure remains elusive, empirical guidelines for assembling molecules into preordained crystal architectures are emerging rapidly. This article briefly describes the current state of the field, emphasizing the design of crystalline materials with structures reinforced by a twodimensional hydrogen-bonded network, which serves as a platform for the synthesis of a diverse collection of compounds. These include host frameworks with cavities supported by organic “pillars” that can be interchanged to manipulate the size, shape, and character of the inclusion cavities as well as the overall lattice architecture and metrics. This research has revealed some principles for crystal design that may prove useful in general while enabling exploration of the utility of these compounds.

A 12-residue peptide designed to form an α-helix and self-associate into an antiparallel 4-α-helical bundle yields a 0.9 Å crystal structure revealing unanticipated features. The structure was determined by direct phasing with the “Shake-and-Bake” program, and contains four crystallographically distinct 12-mer peptide molecules plus solvent for a total of 479 atoms. The crystal is formed from nearly ideal α-helices hydrogen bonded head-to-tail into columns, which in turn pack side-by-side into sheets spanning the width of the crystal. Within each sheet, the α-helices run antiparallel and are closely spaced (9–10 Å center-to-center). The sheets are more loosely packed against each other (13–14 Å between helix centers). Each sheet is amphiphilic: apolar leucine side chains project from one face, charged lysine and glutamate side chains from the other face. The sheets are stacked with two polar faces opposing and two apolar faces opposing. The result is a periodic biomaterial composed of packed protein bilayers, with alternating polar and apolar interfaces. All of the 30 water molecules in the unit cell lie in the polar interface or between the stacked termini of helices. A section through the sheet reveals that the helices packed at the apolar interface resemble the four-α-helical bundle of the design, but the helices overhang parts of the adjacent bundles, and the helix crossing angles are less steep than intended (7–11° rather than 18°).