A Geometric Definition of Short to Medium Range Hydrogen-Mediated Interactions in Proteins

Merski, M.; Skrzeczkowski, Jakub; Roth, Jennifer K; Górna, Maria W.

doi:10.3390/molecules25225326

Cited by 11 publications

(13 citation statements)

References 62 publications

(139 reference statements)

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“…However, hydrogen bonds involving sulfur have negligible, yet context‐specific occurrence (Table S25). Nevertheless, the identification of sulfur‐mediated hydrogen bonds in RNA‐protein complexes further substantiate the putative role of the sulfur atom in biomolecular recognition [44–46,49] . More importantly, in synchrony with a previous study, [24] our analysis highlights the statistically‐important role of carbon‐mediated hydrogen bonds in RNA : protein recognition.…”

Section: Resultssupporting

confidence: 87%

“…Further, variable criteria have been used in literature for the detection of sulfur-mediated hydrogen bonds in the crystal structure of biomacromolecules. [44][45][46] However, our previous quantum-chemical studies suggest that such hydrogen bonds involve DÀ A distance of less than 3 Å. [26] Therefore, in synchrony with the HBPLUS [43] program, we used a consistent criterion for the detection of all polar hydrogen bonds, including sulfur-mediated interactions.…”

Section: Methodsmentioning

confidence: 99%

“…Specifically, we identified the hydrogen bonds using the D−A distance, H−A distance and D−H−A angle cut‐offs of 3.35 Å, 2.7 Å and 90° respectively. Further, variable criteria have been used in literature for the detection of sulfur‐mediated hydrogen bonds in the crystal structure of biomacromolecules [44–46] . However, our previous quantum‐chemical studies suggest that such hydrogen bonds involve D−A distance of less than 3 Å [26] .…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Nature of Hydrogen Bonding between RNA and Proteins: A Comprehensive Analysis of RNA : Protein Complexes

2021

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A nonredundant dataset of ∼300 high (up to 2.5 Å) resolution X‐ray structures of RNA : protein complexes were analyzed for hydrogen bonds between amino‐acid residues and canonical ribonucleotides (rNs). The identified 17100 contacts were classified based on the identity (rA, rC, rG or rU) and interacting fragment (base, sugar, or ribose) of the rN, the nature (polar or nonpolar) and interacting moiety (main chain or side chain) of the amino‐acid residue, as well as the rN and amino‐acid atoms participating in the hydrogen bonding. 80 possible hydrogen‐bonding combinations (4 (rNs)×20 (amino acids)) involve a wide variety of RNA and protein types and are present in multiple occurrences in almost all PDB files. Comparison with the analogously‐selected DNA:protein complexes reveals that the absence of 2′‐OH group in DNA mainly accounts for the differences in DNA:protein and RNA : protein hydrogen bonding. Search for intrinsically‐stable base:amino acid pairs containing single or multiple hydrogen bonds reveals 37 unique pairs, which may act as well‐defined RNA : protein interaction motifs. Overall, our work collectively analyzes the largest set of nucleic acid‐protein hydrogen bonds to date, and therefore highlights several trends that may help frame structural rules governing the physiochemical characteristics of RNA : protein recognition.

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Section: Resultssupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring the Nature of Hydrogen Bonding between RNA and Proteins: A Comprehensive Analysis of RNA : Protein Complexes

2021

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“…Hydrogen bonds are ubiquitous and central to protein folding, molecular recognition, and enzyme catalysis and have been studied broadly using high-resolution protein crystal structures, with the vast majority obtained via cryo X-ray crystallography (63)(64)(65)(66)(67)(68)(69)(70)(71)(72). Given the importance of hydrogen bonds, we used our high-resolution structural data to appraise the effects of X-ray damage on hydrogen bond lengths.…”

Section: Comparison Of Hydrogen Bonds From Room Temperature and Cryo X-ray Datamentioning

confidence: 99%

Damaged goods? Evaluating the impact of X-ray damage on conformational heterogeneity in room temperature and cryo-cooled protein crystals

Yabukarski

Doukov

Mokhtari

et al. 2021

Preprint

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X-ray crystallography is a cornerstone of biochemistry. Traditional freezing of protein crystals to cryo-temperatures mitigates X-ray damage and facilitates crystal handling but provides an incomplete window into the ensemble of conformations at the heart of protein function and energetics. Room temperature (RT) X-ray crystallography provides more extensive ensemble information, and recent developments allow conformational heterogeneity, the experimental manifestation of ensembles, to be extracted from single crystal data. However, high sensitivity to X-ray damage at RT raises concerns about data reliability. To systematically address this critical question, we obtained increasingly X-ray-damaged high-resolution datasets (1.02–1.52 Å) from single thaumatin, proteinase K, and lysozyme crystals. Heterogeneity analyses indicated a modest increase in conformational disorder with X-ray damage. Nevertheless, these effects do not alter overall conclusions and can be minimized by limiting the extent of X-ray damage or eliminated by extrapolation to obtain heterogeneity information free from X-ray damage effects. To compare these effects to damage at cryo temperature and to learn more about damage and heterogeneity in cryo-cooled crystals, we carried out an analogous analysis of increasingly damaged proteinase K cryo datasets (0.9–1.16 Å). We found X-ray damage-associated heterogeneity changes that were not observed at RT. This observation and the scarcity of reported X-ray doses and damage extent render it difficult to distinguish real from artifactual conformations, including those occurring as a function of temperature. The ability to aquire reliable heterogeneity information from single crystals at RT provides strong motivation for further development and routine implementation of RT X-ray crystallography to obtain conformational ensemble information.

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“…In addition, F1068M and F1074M might allow transient polar interactions (80,81). Strikingly, one of the critical phenylalanines coordinating permeating anions in the Fluc-Ec2 channel can only be functionally replaced by methionine (82).…”

Section: Methionine Substitutions At Positions F1068 and F1074mentioning

confidence: 99%

Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains

Prins

Corradi

Sheppard

et al. 2021

Preprint

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Deletion of phenylalanine 508 (F508del), in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, is the most common cause of cystic fibrosis (CF). F508 is located on nucleotide-binding domain 1 (NBD1) in contact with cytosolic extensions of transmembrane helices, in particular intracellular loop 4 (ICL4). We carried out a mutagenesis scan of ICL4 by introducing five or six second-site mutations at eleven positions in cis with F508del, and quantifying changes in membrane proximity and ion-channel function of CFTR. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains, (F1068, R1070W, and F1074, mimicking F1068, F508 and F1074 in wild-type CFTR). F508del-CFTR had a distorted aromatic stack, with F1068 displaced towards space vacated by F508. In F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds, and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR are F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. Finally, two mutations identified in a yeast scan (A141S and R1097T, on adjacent transmembrane helices linked to ICL1 and ICL4) also partially rescued F508del-CFTR function. These studies highlight the importance of hydrophobic interactions and conformational flexibility at the ICL4/NBD1 interface, advancing understanding of the structural underpinning of F508del dysfunction.

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A Geometric Definition of Short to Medium Range Hydrogen-Mediated Interactions in Proteins

Cited by 11 publications

References 62 publications

Exploring the Nature of Hydrogen Bonding between RNA and Proteins: A Comprehensive Analysis of RNA : Protein Complexes

Exploring the Nature of Hydrogen Bonding between RNA and Proteins: A Comprehensive Analysis of RNA : Protein Complexes

Damaged goods? Evaluating the impact of X-ray damage on conformational heterogeneity in room temperature and cryo-cooled protein crystals

Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains

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