Evidence of Water Molecules—A Statistical Evaluation of Water Molecules Based on Electron Density

Nittinger, Eva; Schneider, Nadine; Lange, Gudrun; Rarey, Matthias

doi:10.1021/ci500662d

Cited by 51 publications

(59 citation statements)

References 70 publications

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“…the real-space correlation coefficient (29) or the real-space difference density Z-score (30). Recently, we developed the electron density score for individual atoms (EDIA) (31) as a measure for estimating how well each atom position in a certain structure is supported by the experimental electron density. For all life scientists basing their research on individual structural features of a protein or a nucleic acid, it is essential to know this degree of experimental support for each atom, functional group or ligand molecule.…”

Section: The Proteinsplus Servermentioning

confidence: 99%

ProteinsPlus: a web portal for structure analysis of macromolecules

Fährrolfes

Bietz

Flachsenberg

et al. 2017

Nucleic Acids Research

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182

116

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With currently more than 126 000 publicly available structures and an increasing growth rate, the Protein Data Bank constitutes a rich data source for structure-driven research in fields like drug discovery, crop science and biotechnology in general. Typical workflows in these areas involve manifold computational tools for the analysis and prediction of molecular functions. Here, we present the ProteinsPlus web server that offers a unified easy-to-use interface to a broad range of tools for the early phase of structure-based molecular modeling. This includes solutions for commonly required pre-processing tasks like structure quality assessment (EDIA), hydrogen placement (Protoss) and the search for alternative conformations (SIENA). Beyond that, it also addresses frequent problems as the generation of 2D-interaction diagrams (PoseView), protein–protein interface classification (HyPPI) as well as automatic pocket detection and druggablity assessment (DoGSiteScorer). The unified ProteinsPlus interface covering all featured approaches provides various facilities for intuitive input and result visualization, case-specific parameterization and download options for further processing. Moreover, its generalized workflow allows the user a quick familiarization with the different tools. ProteinsPlus also stores the calculated results temporarily for future request and thus facilitates convenient result communication and re-access. The server is freely available at http://proteins.plus.

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Section: The Proteinsplus Servermentioning

confidence: 99%

ProteinsPlus: a web portal for structure analysis of macromolecules

Fährrolfes

Bietz

Flachsenberg

et al. 2017

Nucleic Acids Research

Self Cite

182

116

View full text Add to dashboard Cite

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“…A recently published statistical analysis of 2.3 million water molecules found that close to 40% of captured (buried) waters with clear electron density made no hydrogen bond with a neighboring water. 70 In Figure 6, waters capable of making hydrogen bonds with two or more other crystallographic waters are plotted as squares. These tend to lie further from the regression line between SZMAP n_ddG and RETI ∆Gabs than other waters.…”

Section: Resultsmentioning

confidence: 99%

Evaluating Free Energies of Binding and Conservation of Crystallographic Waters Using SZMAP

Bayden

Moustakas

Joseph‐McCarthy

et al. 2015

J. Chem. Inf. Model.

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The SZMAP method computes binding free energies and the corresponding thermodynamic components for water molecules in the binding site of a protein structure [ SZMAP, 1.0.0 ; OpenEye Scientific Software Inc. : Santa Fe, NM, USA , 2011 ]. In this work, the ability of SZMAP to predict water structure and thermodynamic stability is examined for the X-ray crystal structures of a series of protein-ligand complexes. SZMAP results correlate with higher-level replica exchange thermodynamic integration double decoupling calculations of the absolute free energy of bound waters in the test set complexes. In addition, SZMAP calculations show good agreement with experimental data in terms of water conservation (across multiple crystal structures) and B-factors over a subset of the test set. In particular, the SZMAP neutral entropy difference term calculated at crystallographic water positions within each of the complex structures correlates well with whether that crystallographic water is conserved or displaceable. Furthermore, the calculated entropy of the water probe relative to the continuum shows a significant degree of correlation with the B-factors associated with the oxygen atoms of the water molecules. Taken together, these results indicate that SZMAP is capable of quantitatively predicting water positions and their energetics and is potentially a useful tool for determining which waters to attempt to displace, maintain, or build in through water-mediated interactions when evolving a lead series during a drug discovery program.

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“…For our new developed cross‐mutation experiment, we compiled a new data set. The PDB structures were selected from the same data set of high‐quality crystal structures as above (criteria: high resolution (≤1.5 Å) and electron density data available) . Within this data set, we searched for pairs of homologous proteins deviating only by 1 (single) to 5 (multiple) mutations with the tool SIENA .…”

Section: Methodsmentioning

confidence: 99%

Prediction of protein mutation effects based on dehydration and hydrogen bonding – A large‐scale study

et al. 2017

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Reliable computational prediction of protein side chain conformations and the energetic impact of amino acid mutations are the key aspects for the optimization of biotechnologically relevant enzymatic reactions using structure-based design. By improving the protein stability, higher yields can be achieved. In addition, tuning the substrate selectivity of an enzymatic reaction by directed mutagenesis can lead to higher turnover rates. This work presents a novel approach to predict the conformation of a side chain mutation along with the energetic effect on the protein structure. The HYDE scoring concept applied here describes the molecular interactions primarily by evaluating the effect of dehydration and hydrogen bonding on molecular structures in aqueous solution. Here, we evaluate its capability of side-chain conformation prediction in classic remutation experiments. Furthermore, we present a new data set for evaluating "cross-mutations," a new experiment that resembles real-world application scenarios more closely. This data set consists of protein pairs with up to five point mutations. Thus, structural changes are attributed to point mutations only. In the cross-mutation experiment, the original protein structure is mutated with the aim to predict the structure of the side chain as in the paired mutated structure. The comparison of side chain conformation prediction ("remutation") showed that the performance of HYDE is qualitatively comparable to state-of-the art methods. The ability of HYDE to predict the energetic effect of a mutation is evaluated in the third experiment. Herein, the effect on protein stability is predicted correctly in 70% of the evaluated cases. Proteins 2017; 85:1550-1566. © 2017 Wiley Periodicals, Inc.

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Evidence of Water Molecules—A Statistical Evaluation of Water Molecules Based on Electron Density

Cited by 51 publications

References 70 publications

ProteinsPlus: a web portal for structure analysis of macromolecules

ProteinsPlus: a web portal for structure analysis of macromolecules

Evaluating Free Energies of Binding and Conservation of Crystallographic Waters Using SZMAP

Prediction of protein mutation effects based on dehydration and hydrogen bonding – A large‐scale study

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