The Role of Small Molecule Additives and Chemical Modification in Protein Crystallization

McPherson, A.; Nguyen, C.; Cudney, Robert; Larson, Steven B.

doi:10.1021/cg101308r

Cited by 48 publications

(44 citation statements)

References 33 publications

(64 reference statements)

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“…Interestingly, the calorimetric approaches, discussed above, arrived at the same conclusion . This is in line with the working hypothesis tested by Alex McPherson, according to which additives promote crystallization by enhancing intermolecular contacts between proteins or by removing such contacts between proteins or solvent .…”

Section: Crystallogenesis In the Era Of Technologies And Structural Gsupporting

confidence: 75%

A historical perspective on protein crystallization from 1840 to the present day

Giegé

2013

FEBS J

106

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Protein crystallization has been known since 1840 and can prove to be straightforward but, in most cases, it constitutes a real bottleneck. This stimulated the birth of the biocrystallogenesis field with both ‘practical’ and ‘basic’ science aims. In the early years of biochemistry, crystallization was a tool for the preparation of biological substances. Today, biocrystallogenesis aims to provide efficient methods for crystal fabrication and a means to optimize crystal quality for X‐ray crystallography. The historical development of crystallization methods for structural biology occurred first in conjunction with that of biochemical and genetic methods for macromolecule production, then with the development of structure determination methodologies and, recently, with routine access to synchrotron X‐ray sources. Previously, the identification of conditions that sustain crystal growth occurred mostly empirically but, in recent decades, this has moved progressively towards more rationality as a result of a deeper understanding of the physical chemistry of protein crystal growth and the use of idea‐driven screening and high‐throughput procedures. Protein and nucleic acid engineering procedures to facilitate crystallization, as well as crystallization methods in gelled‐media or by counter‐diffusion, represent recent important achievements, although the underlying concepts are old. The new nanotechnologies have brought a significant improvement in the practice of protein crystallization. Today, the increasing number of crystal structures deposited in the Protein Data Bank could mean that crystallization is no longer a bottleneck. This is not the case, however, because structural biology projects always become more challenging and thereby require adapted methods to enable the growth of the appropriate crystals, notably macromolecular assemblages.

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Section: Crystallogenesis In the Era Of Technologies And Structural Gsupporting

confidence: 75%

A historical perspective on protein crystallization from 1840 to the present day

Giegé

2013

FEBS J

106

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“…Since the pioneering studies on additive effects on protein crystal growth [36,46,47], the use of these molecules has become extremely widespread. In the literature many papers discuss the action and the effects of these substances on the protein crystallizability and very recently McPherson et al have suggested that these small reagents, and their combinations, may play a primary role in the crystallization process [35]. …”

Section: Factors Affecting Crystallization Of Bio-macromoleculesmentioning

confidence: 99%

An Overview of Biological Macromolecule Crystallization

Krauss

Merlino

Vergara

et al. 2013

IJMS

123

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The elucidation of the three dimensional structure of biological macromolecules has provided an important contribution to our current understanding of many basic mechanisms involved in life processes. This enormous impact largely results from the ability of X-ray crystallography to provide accurate structural details at atomic resolution that are a prerequisite for a deeper insight on the way in which bio-macromolecules interact with each other to build up supramolecular nano-machines capable of performing specialized biological functions. With the advent of high-energy synchrotron sources and the development of sophisticated software to solve X-ray and neutron crystal structures of large molecules, the crystallization step has become even more the bottleneck of a successful structure determination. This review introduces the general aspects of protein crystallization, summarizes conventional and innovative crystallization methods and focuses on the new strategies utilized to improve the success rate of experiments and increase crystal diffraction quality.

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“…[103,104]). Here we are primarily interested in methods that modify very specific patches to achieve the potential for cohesive interactions, driving the formation of crystal contacts.…”

Section: Target Protein Modification For Enhanced Crystallizabilitymentioning

confidence: 99%

The “Sticky Patch” Model of Crystallization and Modification of Proteins for Enhanced Crystallizability

Derewenda

Godzik

2017

Methods in Molecular Biology

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Crystallization of macromolecules has long been perceived as a stochastic process, which cannot be predicted or controlled. This is consistent with another popular notion that the interactions of molecules within the crystal, i.e. crystal contacts, are essentially random and devoid of specific physicochemical features. In contrast, functionally relevant surfaces, such as oligomerization interfaces and specific protein-protein interaction sites, are under evolutionary pressures so their amino acid composition, structure and topology are distinct. However, current theoretical and experimental studies are significantly changing our understanding of the nature of crystallization. The increasingly popular ‘sticky patch’ model, derived from soft matter physics, describes crystallization as a process driven by interactions between select, specific surface patches, with properties thermodynamically favorable for cohesive interactions. Independent support for this model comes from various sources including structural studies and bioinformatics. Proteins that are recalcitrant to crystallization can be modified for enhanced crystallizability through chemical or mutational modification of their surface to effectively engineer ‘sticky patches’ which would drive crystallization. Here, we discuss the current state of knowledge of the relationship between the microscopic properties of the target macromolecule and its crystallizability, focusing on the ‘sticky patch’ model. We discuss state-of-art in silico methods that evaluate the propensity of a given target protein to form crystals based on these relationships, with the objective to design of variants with modified molecular surface properties and enhanced crystallization propensity. We illustrate this discussion with specific cases where these approaches allowed to generate crystals suitable for structural analysis.

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The Role of Small Molecule Additives and Chemical Modification in Protein Crystallization

Cited by 48 publications

References 33 publications

A historical perspective on protein crystallization from 1840 to the present day

A historical perspective on protein crystallization from 1840 to the present day

An Overview of Biological Macromolecule Crystallization

The “Sticky Patch” Model of Crystallization and Modification of Proteins for Enhanced Crystallizability

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