Accurate macromolecular crystallographic refinement: incorporation of the linear scaling, semiempirical quantum-mechanics program<i>DivCon</i>into the<i>PHENIX</i>refinement package

Borbulevych, O.Y.; Plumley, Joshua A.; Martin, Roger I.; Merz, Kenneth M.; Westerhoff, Lance M.

doi:10.1107/s1399004714002260

Cited by 51 publications

(86 citation statements)

References 63 publications

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“…[142,143] In 2004, ar elated approach was presented, in which a linear-scaling semiempiricalQ Mm ethod was employedf or the entire protein, obtained by simplyr eplacing E MM in Equation (7) by E QM . [52,138,144] Chem. This approach has later been extended to other software, including also QM/MM and ab initio methods.…”

Section: Wavefunction-based Refinementmentioning

confidence: 99%

Quantum Crystallography: Current Developments and Future Perspectives

Genoni

Bučinský

Claiser

et al. 2018

Chemistry A European J

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127

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Crystallography and quantum mechanics have always been tightly connected because reliable quantum mechanical models are needed to determine crystal structures. Due to this natural synergy, nowadays accurate distributions of electrons in space can be obtained from diffraction and scattering experiments. In the original definition of quantum crystallography (QCr) given by Massa, Karle and Huang, direct extraction of wavefunctions or density matrices from measured intensities of reflections or, conversely, ad hoc quantum mechanical calculations to enhance the accuracy of the crystallographic refinement are implicated. Nevertheless, many other active and emerging research areas involving quantum mechanics and scattering experiments are not covered by the original definition although they enable to observe and explain quantum phenomena as accurately and successfully as the original strategies. Therefore, we give an overview over current research that is related to a broader notion of QCr, and discuss options how QCr can evolve to become a complete and independent domain of natural sciences. The goal of this paper is to initiate discussions around QCr, but not to find a final definition of the field.

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Section: Wavefunction-based Refinementmentioning

confidence: 99%

Quantum Crystallography: Current Developments and Future Perspectives

Genoni

Bučinský

Claiser

et al. 2018

Chemistry A European J

Self Cite

127

114

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“…While PDB_Redo (Cereto- Massagué et al, 2013) has shown that improvements to the quality of the model can be made, we have shown that there is a limit, when using restraint dictionaries, to how much of an improvement can be made to ligand conformation energy and geometry. As a move is made to obtain more accurate models, it is our hope that refinement target functions will more often be implemented according to the paradigm presented here (Borbulevych, Plumley et al, 2014;Smart et al, 2010Smart et al, , 2014) so as to more accurately represent the complex conformational space of small-molecule ligands.…”

Section: Discussionmentioning

confidence: 99%

“…The latter approaches are often complicated to use, requiring multiple additional steps from the user. They are therefore difficult to integrate into an automated workflow and the speed requirements of many modern-day high-throughput laboratories such as those involved in pharmaceutical drug discovery (Borbulevych et al, 2016;Borbulevych, Plumley et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…We have chosen to only compare refinement using AFITT-derived CIF restraint dictionaries versus obtaining the ligand geometry gradients in refinement directly from AFITT (PHENIX-AFITT). Thus, our comparison is not complicated by differences in potential functions and target values for the methods used by various other ligand restraint-file generation and modeling methods (Borbulevych, Moriarty et al, 2014;Borbulevych, Plumley, et al, 2014;Davis et al, 2003;Fu et al, 2011;Lebedev et al, 2012;Moriarty et al, 2009;Schü ttelkopf & van Aalten, 2004;Smart et al, 2010Smart et al, , 2012Yu et al, 2005). Instead, differences hinge only on the improvement gained by representing the ligand with the full molecular-mechanics force field during the course of refinement.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Improved ligand geometries in crystallographic refinement usingAFITTinPHENIX

Janowski

Moriarty

Kelley

et al. 2016

Acta Crystallogr D Struct Biol

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Modern crystal structure refinement programs rely on geometry restraints to overcome the challenge of a low data-to-parameter ratio. While the classical Engh and Huber restraints work well for standard amino-acid residues, the chemical complexity of small-molecule ligands presents a particular challenge. Most current approaches either limit ligand restraints to those that can be readily described in the Crystallographic Information File (CIF) format, thus sacrificing chemical flexibility and energetic accuracy, or they employ protocols that substantially lengthen the refinement time, potentially hindering rapid automated refinement workflows. PHENIX-AFITT refinement uses a full molecular-mechanics force field for user-selected small-molecule ligands during refinement, eliminating the potentially difficult problem of finding or generating high-quality geometry restraints. It is fully integrated with a standard refinement protocol and requires practically no additional steps from the user, making it ideal for high-throughput workflows. PHENIX-AFITT refinements also handle multiple ligands in a single model, alternate conformations and covalently bound ligands. Here, the results of combining AFITT and the PHENIX software suite on a data set of 189 protein-ligand PDB structures are presented. Refinements using PHENIX-AFITT significantly reduce ligand conformational energy and lead to improved geometries without detriment to the fit to the experimental data. For the data presented, PHENIX-AFITT refinements result in more chemically accurate models for small-molecule ligands.

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“…Two studies using quantum calculations to evaluate ligand strain provide more evidence that this problem is pervasive. 4,6 ■ COMMON ISSUES How can so many bound-ligand structures have problems? There are many reasons.…”

Section: ■ Evidence Of a Problemmentioning

confidence: 99%

Protein–Ligand Cocrystal Structures: We Can Do Better

Reynolds¹

2014

ACS Med. Chem. Lett.

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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. KEYWORDS: Protein−ligand cocrystal, structure-induced fit, structure-based design, structure refinement, bound ligand strain T he ability to accurately determine the 3D structure of protein−ligand complexes using X-ray crystallography has provided an important tool for drug discovery. The number of publicly available structures in the RCSB PDB (www.pdb.org) has grown to almost 100,000, and of course this does not include the many thousands of proprietary structures that have been determined. During this growth there have been numerous studies that raise concerns about the fidelity of many of these structures with regard to the bound ligand. 1−4 They all find that many bound ligands in the PDB incorporate a surprising amount of internal strain. Further, inspection of these structures shows a litany of distorted rings, bad contacts, and unusual conformations/configurations. In short, the prevailing literature suggests that current refinement procedures often do a poor job of correctly refining the bound ligand. ■ EVIDENCE OF A PROBLEMJust to give a few examples: 1xqd contains three planar oxygens as part of a phosphate group; 1pme features a planar sulfur in the sulfoxide; 1tnk, a 1.8 Å resolution structure, contains a nonplanar tetrahedral aromatic carbon as part of a substituted aniline; and 4g93 contains an olefin that is twisted nearly 90°o ut of the plane. While it is surprising that such egregious chemical structures could find their way into the literature much less the PDB, we might dismiss them as anomalies. However, the truth is any systematic evaluation of the bound ligands in the PDB will uncover countless, less dramatic, albeit still serious structural errors. While the tone of some early work seems to be more in the direction of attempting to explain this phenomenon, 1 there has gradually been a widespread realization that induced fit cannot explain the large number of strained and distorted ligands.Studies of bound ligand strain commonly entail assembling a selection of cocrystal structures from the PDB, extracting the bound ligand, and then optimizing the ligand outside the confines of the protein active site. While this sounds simple, there are many important computational details that can have a significant effect on the results. For example, selection of the bound and free reference states, inclusion of solvation (or other medium effects), and the model employed (e.g., force field or quantum). The most common measures of bound ligand strain are usually referred to as local or global strain as defined in eqs 1 and 2, respectively.The first definition (eq 1) is problematic in that it demands extensive conformational analysis ...

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Accurate macromolecular crystallographic refinement: incorporation of the linear scaling, semiempirical quantum-mechanics programDivConinto thePHENIXrefinement package

Cited by 51 publications

References 63 publications

Quantum Crystallography: Current Developments and Future Perspectives

Quantum Crystallography: Current Developments and Future Perspectives

Improved ligand geometries in crystallographic refinement usingAFITTinPHENIX

Protein–Ligand Cocrystal Structures: We Can Do Better

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