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Hybrid Methods for Structural Biology and Drug Design: A Memorial...
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Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 7972

Special Issue Editor

Dr. Brad C. Bennett

E-Mail Website
Guest Editor
Biological and Environmental Science Department, Howard College of Arts and Sciences, Samford University, Birmingham, AL 35229, USA
Interests: structural biology; antibiotic drug design; human membrane proteins; probiotic metabolites; molecular microbiology; microbial evolution
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Like you, I was surprised and saddened by the untimely death of Dr. Chris Dealwis, Associate Professor of Pharmacology at Case Western Reserve University (CWRU), in July 2022. He was my Ph.D. mentor, and I continued to collaborate with him until his death. Chris pursued high-resolution structural biology and worked on several important macromolecular structures, including renin, chemokines, amyloid-recognizing antibodies, ribonucleotide reductase, and dihydrofolate reductase. He was especially interested in and talented at applying a plethora of structural methods, including X-ray and neutron crystallography, mass spectrometry, and fluorescence spectroscopy, among others, to probe complex biological assemblies, inform drug design strategies, and address fundamental biochemical problems.

We are pleased to invite you to contribute an article to a special memorial issue that will serve to celebrate Chris’s scientific life and work.

This Special Issue aims to highlight all manner of biochemical and biophysical methods, such as the ones listed above, that are used to elucidate the macromolecular structure and/or evaluate protein targets for drug design efforts. This appreciation and blend of disparate methods to answer important biological questions reflect Chris’s successful scientific career.

Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: Structural Biology, Medicinal Chemistry, Pharmacology, Molecular Biology, Biochemistry, Biophysical Chemistry, and methods developed for any of the areas listed here. Additionally, any reflections on Chris and his work may be included in your article if appropriate.

Thank you for your consideration, and I look forward to receiving your contributions.

Dr. Brad C. Bennett
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • structural biology
  • crystallography
  • spectroscopy
  • neutron diffraction
  • enzyme mechanism
  • drug design
  • cancer chemotherapy
  • protein dynamics
  • electron microscopy

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Published Papers (4 papers)

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Research

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14 pages, 2732 KiB  
Article
Novel Covalent Modifier-Induced Local Conformational Changes within the Intrinsically Disordered Region of the Androgen Receptor
by Michael T. Harnish, Daniel Lopez, Corbin T. Morrison, Ramesh Narayanan, Elias J. Fernandez and Tongye Shen
Biology 2023, 12(11), 1442; https://doi.org/10.3390/biology12111442 - 17 Nov 2023
Cited by 1 | Viewed by 1929
Abstract
Intrinsically disordered regions (IDRs) of transcription factors play an important biological role in liquid condensate formation and gene regulation. It is thus desirable to investigate the druggability of IDRs and how small-molecule binders can alter their conformational stability. For the androgen receptor (AR), [...] Read more.
Intrinsically disordered regions (IDRs) of transcription factors play an important biological role in liquid condensate formation and gene regulation. It is thus desirable to investigate the druggability of IDRs and how small-molecule binders can alter their conformational stability. For the androgen receptor (AR), certain covalent ligands induce important changes, such as the neutralization of the condensate. To understand the specificity of ligand–IDR interaction and potential implications for the mechanism of neutralizing liquid–liquid phase separation (LLPS), we modeled and performed computer simulations of ligand-bound peptide segments obtained from the human AR. We analyzed how different covalent ligands affect local secondary structure, protein contact map, and protein–ligand contacts for these protein systems. We find that effective neutralizers make specific interactions (such as those between cyanopyrazole and tryptophan) that alter the helical propensity of the peptide segments. These findings on the mechanism of action can be useful for designing molecules that influence IDR structure and condensate of the AR in the future. Full article
(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)
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Review

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15 pages, 2765 KiB  
Review
“Seeing Is Believing”: How Neutron Crystallography Informs Enzyme Mechanisms by Visualizing Unique Water Species
by Qun Wan and Brad C. Bennett
Biology 2024, 13(11), 850; https://doi.org/10.3390/biology13110850 - 22 Oct 2024
Viewed by 547
Abstract
Hydrogen is the lightest atom and composes approximately half of the atomic content in macromolecules, yet their location can only be inferred or predicted in most macromolecular structures. This is because hydrogen can rarely be directly observed by the most common structure determination [...] Read more.
Hydrogen is the lightest atom and composes approximately half of the atomic content in macromolecules, yet their location can only be inferred or predicted in most macromolecular structures. This is because hydrogen can rarely be directly observed by the most common structure determination techniques (such as X-ray crystallography and electron cryomicroscopy). However, knowledge of hydrogen atom positions, especially for enzymes, can reveal protonation states of titratable active site residues, hydrogen bonding patterns, and the orientation of water molecules. Though we know they are present, this vital layer of information, which can inform a myriad of biological processes, is frustratingly invisible to us. The good news is that, even at modest resolution, neutron crystallography (NC) can reveal this layer and has emerged this century as a powerful tool to elucidate enzyme catalytic mechanisms. Due to its strong and coherent scattering of neutrons, incorporation of deuterium into the protein crystal amplifies the power of NC. This is especially true when solvation and the specific participation of key water molecules are crucial for catalysis. Neutron data allow the modeling of all three atoms in water molecules and have even revealed previously unobserved and unique species such as hydronium (D3O+) and deuteroxide (OD−) ions as well as lone deuterons (D+). Herein, we briefly review why neutrons are ideal probes for identifying catalytically important water molecules and these unique water-like species, limitations in interpretation, and four vignettes of enzyme success stories from disparate research groups. One of these groups was that of Dr. Chris G. Dealwis, who died unexpectedly in 2022. As a memorial appreciation of his scientific career, we will also highlight his interest and contributions to the neutron crystallography field. As both the authors were mentored by Chris, we feel we have a unique perspective on his love of molecular structure and admiration for neutrons as a tool to query those structures. Full article
(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)
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32 pages, 8389 KiB  
Review
Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures
by Maciej Jagielnicki, Iga Kucharska, Brad C. Bennett, Andrew L. Harris and Mark Yeager
Biology 2024, 13(5), 298; https://doi.org/10.3390/biology13050298 - 26 Apr 2024
Cited by 3 | Viewed by 1934
Abstract
Connexins (Cxs) are a family of integral membrane proteins, which function as both hexameric hemichannels (HCs) and dodecameric gap junction channels (GJCs), behaving as conduits for the electrical and molecular communication between cells and between cells and the extracellular environment, respectively. Their proper [...] Read more.
Connexins (Cxs) are a family of integral membrane proteins, which function as both hexameric hemichannels (HCs) and dodecameric gap junction channels (GJCs), behaving as conduits for the electrical and molecular communication between cells and between cells and the extracellular environment, respectively. Their proper functioning is crucial for many processes, including development, physiology, and response to disease and trauma. Abnormal GJC and HC communication can lead to numerous pathological states including inflammation, skin diseases, deafness, nervous system disorders, and cardiac arrhythmias. Over the last 15 years, high-resolution X-ray and electron cryomicroscopy (cryoEM) structures for seven Cx isoforms have revealed conservation in the four-helix transmembrane (TM) bundle of each subunit; an αβ fold in the disulfide-bonded extracellular loops and inter-subunit hydrogen bonding across the extracellular gap that mediates end-to-end docking to form a tight seal between hexamers in the GJC. Tissue injury is associated with cellular Ca2+ overload. Surprisingly, the binding of 12 Ca2+ ions in the Cx26 GJC results in a novel electrostatic gating mechanism that blocks cation permeation. In contrast, acidic pH during tissue injury elicits association of the N-terminal (NT) domains that sterically blocks the pore in a “ball-and-chain” fashion. The NT domains under physiologic conditions display multiple conformational states, stabilized by protein–protein and protein–lipid interactions, which may relate to gating mechanisms. The cryoEM maps also revealed putative lipid densities within the pore, intercalated among transmembrane α-helices and between protomers, the functions of which are unknown. For the future, time-resolved cryoEM of isolated Cx channels as well as cryotomography of GJCs and HCs in cells and tissues will yield a deeper insight into the mechanisms for channel regulation. The cytoplasmic loop (CL) and C-terminal (CT) domains are divergent in sequence and length, are likely involved in channel regulation, but are not visualized in the high-resolution X-ray and cryoEM maps presumably due to conformational flexibility. We expect that the integrated use of synergistic physicochemical, spectroscopic, biophysical, and computational methods will reveal conformational dynamics relevant to functional states. We anticipate that such a wealth of results under different pathologic conditions will accelerate drug discovery related to Cx channel modulation. Full article
(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)
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19 pages, 3926 KiB  
Review
Significance of Histidine Hydrogen–Deuterium Exchange Mass Spectrometry in Protein Structural Biology
by Masaru Miyagi and Takashi Nakazawa
Biology 2024, 13(1), 37; https://doi.org/10.3390/biology13010037 - 9 Jan 2024
Viewed by 2927
Abstract
Histidine residues play crucial roles in shaping the function and structure of proteins due to their unique ability to act as both acids and bases. In other words, they can serve as proton donors and acceptors at physiological pH. This exceptional property is [...] Read more.
Histidine residues play crucial roles in shaping the function and structure of proteins due to their unique ability to act as both acids and bases. In other words, they can serve as proton donors and acceptors at physiological pH. This exceptional property is attributed to the side-chain imidazole ring of histidine residues. Consequently, determining the acid-base dissociation constant (Ka) of histidine imidazole rings in proteins often yields valuable insights into protein functions. Significant efforts have been dedicated to measuring the pKa values of histidine residues in various proteins, with nuclear magnetic resonance (NMR) spectroscopy being the most commonly used technique. However, NMR-based methods encounter challenges in assigning signals to individual imidazole rings and require a substantial amount of proteins. To address these issues associated with NMR-based approaches, a mass-spectrometry-based method known as histidine hydrogen–deuterium exchange mass spectrometry (His-HDX-MS) has been developed. This technique not only determines the pKa values of histidine imidazole groups but also quantifies their solvent accessibility. His-HDX-MS has proven effective across diverse proteins, showcasing its utility. This review aims to clarify the fundamental principles of His-HDX-MS, detail the experimental workflow, explain data analysis procedures and provide guidance for interpreting the obtained results. Full article
(This article belongs to the Special Issue Hybrid Methods for Structural Biology and Drug Design: A Memorial Issue for Dr. Chris G. Dealwis)
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