Lack of controls
and understanding in nucleation, which proceeds
crystal growth and other phase transitions, has been a bottleneck
challenge in chemistry, materials, biology, and other fields. The
exemplary needs for better methods for biomacromolecule crystallization
include (1) synthesizing crystals for high-resolution structure determinations
in fundamental research and (2) tuning the crystal habit and thus
the corresponding properties in materials and pharmaceutical applications.
Herein, a deterministic method is established capable of sustaining
the nucleation and growth of a single crystal using the protein lysozyme
as a prototype. The supersaturation is localized at the interface
between a sample and a precipitant solution, spatially confined by
the tip of a single nanopipette. The exchange of matter between the
two solutions determines the supersaturation, which is controlled
by electrokinetic ion transport driven by an external potential waveform.
Nucleation and subsequent crystal growth disrupt the ionic current
limited by the nanotip and are detected. The nucleation and growth
of individual single crystals are measured in real time. Electroanalytical
and optical signatures are elucidated as feedbacks with which active
controls in crystal quality and method consistency are achieved: five
out of five crystals diffract at a true atomic resolution of up to
1.2 Å. As controls, those synthesized under less optimized conditions
diffract poorly. The crystal habits during the growth process are
tuned successfully by adjusting the flux. The universal mechanism
of nano-transport kinetics, together with the correlations of the
diffraction quality and crystal habit with the crystallization control
parameters, lay the foundation for the generalization to other materials
systems.