Role of clusters in nonclassical nucleation and growth of protein crystals

Mike Sleutel, Alexander Van Driessche

Research output: Contribution to journalArticlepeer-review

145 Citations (Scopus)


The development of multistep nucleation theory has spurred on
experimentalists to find intermediate metastable states that are
relevant to the solidification pathway of the molecule under
interest. A great deal of studies focused on characterizing the
so-called "precritical clusters" that may arise in the precipitation
process. However, in macromolecular systems, the role that these
clusters might play in the nucleation process and in the second
stage of the precipitation process, i.e., growth, remains to a great
extent unknown. Therefore, using biological macromolecules as
a model system, we have studied the mesoscopic intermediate,
the solid end state, and the relationship that exists between them.
We present experimental evidence that these clusters are liquidlike
and stable with respect to the parent liquid and metastable
compared with the emerging crystalline phase. The presence of
these clusters in the bulk liquid is associated with a nonclassical
mechanism of crystal growth and can trigger a self-purifying cascade
of impurity-poisoned crystal surfaces. These observations
demonstrate that there exists a nontrivial connection between
the growth of the macroscopic crystalline phase and the mesoscopic
intermediate which should not be ignored. On the other
hand, our experimental data also show that clusters existing in
protein solutions can significantly increase the nucleation rate
and therefore play a relevant role in the nucleation process.
Original languageEnglish
Pages (from-to)546–553
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Publication statusPublished - 2014


  • protein crystal nucleation


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