Macromolecular Crystallography for Synthetic Abiological Molecules: Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles

Abhishek Singharoy, Balasubramanian Venkatakrishnan, Yun Liu, Christopher G. Mayne, Semin Lee, Chun Hsing Chen, Adam Zlotnick, Klaus Schulten, Amar H. Flood

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Crystal structure determination has long provided insight into structure and bonding of small molecules. When those same small molecules are designed to come together in multimolecular assemblies, such as in coordination cages, supramolecular architectures and organic-based frameworks, their crystallographic characteristics closely resemble biological macromolecules. This resemblance suggests that biomacromolecular refinement approaches be used for structure determination of abiological molecular complexes that arise in an aggregate state. Following this suggestion we investigated the crystal structure of a pentagonal macrocycle, cyanostar, by means of biological structure analysis methods and compared results to traditional small molecule methods. Cyanostar presents difficulties seen in supramolecular crystallography including whole molecule disorder and highly flexible solvent molecules sitting in macrocyclic and intermolecule void spaces. We used the force-field assisted refinement method, molecular dynamics flexible fitting algorithm for X-ray crystallography (xMDFF), along with tools from the macromolecular structure determination suite PHENIX. We found that a standard implementation of PHENIX, namely one without xMDFF, either fails to produce a solution by molecular replacement alone or produces an inaccurate structure when using generic geometry restraints, even at a very high diffraction data resolution of 0.84 Å. The problems disappear when taking advantage of xMDFF, which applies an optimized force field to realign molecular models during phasing by providing accurate restraints. The structure determination for this model system shows excellent agreement with the small-molecule methods. Therefore, the joint xMDFF-PHENIX refinement protocol provides a new strategy that uses macromolecule methods for structure determination of small molecules and their assemblies.

Original languageEnglish (US)
Pages (from-to)8810-8818
Number of pages9
JournalJournal of the American Chemical Society
Volume137
Issue number27
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

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Crystallography
Molecules
Macromolecules
Molecular Models
X Ray Crystallography
Crystal structure
Molecular Dynamics Simulation
X ray crystallography
Joints
Molecular dynamics
Diffraction
Geometry

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Macromolecular Crystallography for Synthetic Abiological Molecules : Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles. / Singharoy, Abhishek; Venkatakrishnan, Balasubramanian; Liu, Yun; Mayne, Christopher G.; Lee, Semin; Chen, Chun Hsing; Zlotnick, Adam; Schulten, Klaus; Flood, Amar H.

In: Journal of the American Chemical Society, Vol. 137, No. 27, 15.07.2015, p. 8810-8818.

Research output: Contribution to journalArticle

Singharoy, Abhishek ; Venkatakrishnan, Balasubramanian ; Liu, Yun ; Mayne, Christopher G. ; Lee, Semin ; Chen, Chun Hsing ; Zlotnick, Adam ; Schulten, Klaus ; Flood, Amar H. / Macromolecular Crystallography for Synthetic Abiological Molecules : Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles. In: Journal of the American Chemical Society. 2015 ; Vol. 137, No. 27. pp. 8810-8818.
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