Fractal Aggregates in Protein Crystal Nucleation

Chen, Bin; Nellas, Ricky B.; Keasler, Samuel J.

doi:10.1021/jp8002728

Cited by 20 publications

(32 citation statements)

References 50 publications

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“…S4). The value of n at which arrest occurs is a function of d : in general, optimal assembly for given d occurs when n is too small to induce the formation of large liquidlike clusters, in accord with a suggestion made on the basis of a study of isotropic model proteins [14]. For certain choices of the specific interaction, however, such as d = 4, yields are maximized close to the liquid-vapor critical region.…”

supporting

confidence: 68%

Control of Pathways and Yields of Protein Crystallization through the Interplay of Nonspecific and Specific Attractions

Whitelam¹

2010

Phys. Rev. Lett.

102

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We use computer simulation to study crystal-forming model proteins equipped with interactions that are both orientationally specific and nonspecific. Distinct dynamical pathways of crystal formation can be selected by tuning the strengths of these interactions. When the nonspecific interaction is strong, liquidlike clustering can precede crystallization; when it is weak, growth can proceed via ordered nuclei. Crystal yields are in certain parameter regimes enhanced by the nonspecific interaction, even though it promotes association without local crystalline order. Our results suggest that equipping nanoscale components with weak nonspecific interactions (such as depletion attractions) can alter both their dynamical pathway of assembly and optimize the yield of the resulting material.

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supporting

confidence: 68%

Control of Pathways and Yields of Protein Crystallization through the Interplay of Nonspecific and Specific Attractions

Whitelam¹

2010

Phys. Rev. Lett.

102

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“…In molecular dynamics simulations the free energies of association can be computed using umbrella sampling or metadynamics, but these methods require the identification of one or a set of collective variables to span the ''reactive'' subspace of the chemical system under investigation. With the exception of simple molecular systems, such as tetrolic acid, 17 the choice of collective variables associated with the molecular selfassembly process of organic molecules is not always obvious. Moreover, MD simulations of organic molecules in explicit solvent molecules usually rely on classical molecular mechanics force fields, which are unable to account for electronic polarization or proton transfer.…”

Section: Introductionmentioning

confidence: 99%

The molecular self-association of carboxylic acids in solution: testing the validity of the link hypothesis using a quantum mechanical continuum solvation approach

Tommaso

2013

CrystEngComm

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The molecular self-association of carboxylic acids in solution: testing the validity of the link hypothesis using a quantum mechanical continuum solvation approach3According to the ''link hypothesis'' there is a connection between the solvent-dependent most stable selfassociated groups of molecules and the building unit present in the polymorph that crystallizes from solution. We have tested this hypothesis by computing the Gibbs free energies for the molecular selfassociation in solution of three selected monocarboxylic acids that crystallize in different polymorphic forms and exhibit selective crystallization depending on the solvent: tetrolic acid (TTA), m-aminobenzoic acid (mABA) and m-hydroxybenzoic acid (mHBA). Calculations have been conducted at the density functional theory (M06-2X) level with the SMD polarizable continuum model to simulate aqueous and organic solutions. For all three systems we have found that the solvation environment significantly affects the stability of dimers. The most stable dimer in solution is the classic carboxylic acid dimer, and its stability decreases on going from nonpolar solvents, such as chloroform or acetonitrile, to aqueous and alcoholic solutions. However, whilst for TTA and mABA there is a link between the carboxylic dimer synthon in solution and the structural synthon packed in the metastable a-TTA polymorph, which crystallizes from chloroform, and in the crystal form-II of mABA, which crystallizes from acetonitrile, for mHBA the stabilization of the centrosymmetric carboxylic dimeric in acetonitrile and ethyl acetate does not correspond with recent experimental observations that the polymorph containing this structural unit (form I) is not the crystal form that nucleates preferentially from these solvents (Cryst. Growth Des., 2013, 13, 1140. Starting from the carboxylic dimer of TTA, the processes of trimerization and tetramerization of TTA from solution have been also modelled. The calculations suggest that the formation of tetramers in chloroform occurs from the self-association of the carboxylic acid dimers and not through the association of the TTA monomers and trimers. The free energy formation of the ionized forms of the mABA dimer (non-zwitterionic-zwitterionic and zwitterionic-zwitterionic) has been evaluated and, according to our results, zwitterionic-zwitterionic mABA dimers might be abundant in supersaturated aqueous and alcoholic solutions of m-aminobenzoic acid.

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“…On average 30-200 curved rod-shaped crystals with a length of around 60 μm were observed per well, together with up to 10 star-shaped fractal crystals with a diameter of around 60 μm. Fractal aggregates can form during nucleation [44], leading to fractal crystals when followed by rapid crystal growth. The fractal crystals were easier to locate because of their size and for this reason the microenvironment around fractal crystals was preferentially chosen for analysis.…”

Section: Resultsmentioning

confidence: 99%

Exploring the in meso crystallization mechanism by characterizing the lipid mesophase microenvironment during the growth of single transmembrane α-helical peptide crystals

Hag

Knoblich

Seabrook

et al. 2016

Phil. Trans. R. Soc. A.

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The proposed mechanism for in meso crystallization of transmembrane proteins suggests that a protein or peptide is initially uniformly dispersed in the lipid self-assembly cubic phase but that crystals grow from a local lamellar phase, which acts as a conduit between the crystal and the bulk cubic phase. However, there is very limited experimental evidence for this theory. We have developed protocols to investigate the lipid mesophase microenvironment during crystal growth using standard procedures readily available in crystallography laboratories. This technique was used to characterize the microenvironment during crystal growth of the DAP12-TM peptide using synchrotron small angle X-ray scattering (SAXS) with a micro-sized X-ray beam. Crystal growth was found to occur from the gyroid cubic mesophase. For one in four crystals, a highly oriented local lamellar phase was observed, providing supporting evidence for the proposed mechanism for in meso crystallization. A new observation of this study was that we can differentiate diffraction peaks from crystals grown in meso, from peaks originating from the surrounding lipid matrix, potentially opening up the possibility of high-throughput SAXS analysis of in meso grown crystals.This article is part of the themed issue 'Soft interfacial materials: from fundamentals to formulation'.

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Fractal Aggregates in Protein Crystal Nucleation

Cited by 20 publications

References 50 publications

Control of Pathways and Yields of Protein Crystallization through the Interplay of Nonspecific and Specific Attractions

Control of Pathways and Yields of Protein Crystallization through the Interplay of Nonspecific and Specific Attractions

The molecular self-association of carboxylic acids in solution: testing the validity of the link hypothesis using a quantum mechanical continuum solvation approach

Exploring the in meso crystallization mechanism by characterizing the lipid mesophase microenvironment during the growth of single transmembrane α-helical peptide crystals

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