All Publications

with tag 'xray'

November 01, 2018
In the present work, this approach is expanded to include a more rigorous treatment of the entire structure, including the ligand(s), the associated active site(s) and the entire protein, using a fully automated, mixed quantum-mechanics/molecular-mechanics (QM/MM) Hamiltonian recently implemented in the DivCon package. This approach was validated through the automatic treatment of a population of 80 protein–ligand structures chosen from the Astex Diverse Set. Across the entire population, this method results in an average 3.5-fold reduction in ligand strain and a 4.5-fold improvement in MolProbity clashscore, as well as improvements in Ramachandran and rotamer outlier analyses. Overall, these results demonstrate that the use of a structure-wide QM/MM Hamiltonian exhibits improvements in the local structural chemistry of the ligand similar to Region-QM refinement but with significant improvements in the overall structure beyond the active site.
April 01, 2016
Gaining an understanding of the protein:ligand complex structure along with the proper protonation and explicit solvent effects can be important in obtaining meaningful results in structure-guided drug discovery and structure-based drug discovery. In the present work, we describe a novel scoring method, called XModeScore, which enumerates the possible protomeric/tautomeric modes, refines each mode against X-ray diffraction data with quantum mechanics and scores each mode using a combination of energetic strain (or ligand strain) and rigorous statistical analysis of the difference electron density distribution.
June 02, 2014
There is a large body of evidence that many protein–ligand cocrystal structures contain poorly refined ligand geometries. These errors result in bound structures that have nonideal bond lengths and angles, are strained, contain improbable conformations, and have bad protein–ligand contacts. Many of these problems can be greatly reduced with better refinement models.
May 01, 2014
Macromolecular crystallographic refinement relies on sometimes dubious stereochemical restraints and rudimentary energy functionals to ensure the correct geometry of the model of the macromolecule and any covalently bound ligand(s).... Stereochemical restraints have been replaced with more robust functionals through the integration of the linear-scaling, semiempirical quantum mechanics (SE-QM) program DivCon with the PHENIX X-ray refinement engine.
April 03, 2014
The impact of QM and QM/MM based X-ray refinement on our understanding of protein:ligand function is discussed in detail with examples including interaction decomposition diagrams, scores, and other values. This information is particularly interesting to structure based drug discovery practitioners.
March 27, 2013
We have provided a demonstration of how to use QM-based X-ray refinement to inform the often difficult choice about where to put a proton. This seemingly simple atom has given practioners in the field a lot of grief over the years, and it turns out that QM-based methods do a really good job of helping you make this important decision!
February 13, 2013
The recognition and association of donepezil with acetylcholinesterase (AChE) has been extensively studied in the past several decades because of the former’s use as a palliative treatment for mild Alzheimer disease. Herein, we examine the conformational properties of donepezil and we re-examine the donepezil-AChE crystal structure using combined quantum mechanical/molecular mechanical (QM/MM) X-ray refinement tools.....
February 24, 2012
The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and 48 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x, and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ, and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets....
November 13, 2011
Retinoic acid (RA) is a vitamin A derivative, which modifies the appearance of fine wrinkles and roughness of facial skin and treats acne and activates gene transcription by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoic X receptor (RXR). There are series of protein bound RA complexes available in the protein databank (PDB), which provides a broad range of information about the different bioactive conformations of RA....
May 19, 2011
An ongoing question regarding the energetics of protein-ligand binding has been; what is the strain energy that a ligand pays (if any) when binding to its protein target? The traditional method to estimate strain energy uses force fields to calculate the energy difference between the ligand bound conformation and its nearest local minimum/global minimum on the gas-phase or aqueous phase potential energy surface....
May 01, 2010
Zinc metalloenzymes play an important role in biology. However, due to the limitation of molecular force field energy restraints used in X-ray refinement at medium or low resolutions, the precise geometry of the zinc coordination environment can be difficult to distinguish from ambiguous electron density maps. Due to the difficulties involved in defining accurate force fields for metal ions...
May 12, 2009
Determining the structure of a small molecule bound to a biological receptor (e.g., a protein implicated in a disease state) is a necessary step in structure-based drug design. The preferred conformation of a small molecule can change when bound to a protein, and a detailed knowledge of the preferred conformation(s) of a bound ligand can help in optimizing the affinity of a molecule for its receptor....
January 18, 2007
December 15, 2005
March 01, 2005
December 10, 2004