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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 18893

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Prof. Dr. Ray Luo

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Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
Interests: computational analysis of biomolecular sequence, structure, dynamics, and function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue, entitled "Recent Advances in Biomolecular Recognition".

Living cells are extremely complicated systems and comprise hundreds of thousands of different biomolecules that interact with each other to maintain fundamental cellular functions. The disruption of these interactions is frequently linked to various human diseases. The interactions, i.e., biomolecular recognitions, are very specific and are mediated by both polar and nonpolar interactions. These important interactions are also mediated strongly by water.

The goal of this Special Issue is to bring together wet- and dry-lab researchers with common interests in biomolecular recognition and to share their research efforts and to seek collaborations addressing common interesting questions. A Special Issue with publications from researchers utilizing and developing different experimental and computational methods would certainly help to reveal the strengths and weaknesses of their approaches and enable one to make further improvements. Potential topics may include protein–protein binding; protein–membrane interactions; protein–nucleic acid interactions; interactions with small molecules and drug design; electrostatics, polarization, and solvation in molecular recognition; and mutations in molecular recognition.

Prof. Dr. Ray Luo
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

proteins
nucleic acids
membrane
ligand
binding

Published Papers (11 papers)

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Editorial

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2 pages, 182 KiB

Open AccessEditorial

Recent Advances in Biomolecular Recognition

by Qiang Zhu and Ray Luo

Int. J. Mol. Sci. 2023, 24(9), 8310; https://doi.org/10.3390/ijms24098310 - 05 May 2023

Viewed by 667

Abstract

Living cells are extremely complicated systems and composed of hundreds of thousands of diverse biomolecules, such as proteins, nucleic acids, and carbohydrates [...] Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

Research

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16 pages, 6139 KiB

Open AccessArticle

Expression and Characterization of Intein-Cyclized Trimer of Staphylococcus aureus Protein A Domain Z

by Suman Nandy, Vijay M. Maranholkar, Mary Crum, Katherine Wasden, Ujwal Patil, Atul Goyal, Binh Vu, Katerina Kourentzi, William Mo, Amy Henrickson, Borries Demeler, Mehmet Sen and Richard C. Willson

Int. J. Mol. Sci. 2023, 24(2), 1281; https://doi.org/10.3390/ijms24021281 - 09 Jan 2023

Cited by 3 | Viewed by 2628

Abstract

Staphylococcus aureus protein A (SpA) is an IgG Fc-binding virulence factor that is widely used in antibody purification and as a scaffold to develop affinity molecules. A cyclized SpA Z domain could offer exopeptidase resistance, reduced chromatographic ligand leaching after single-site endopeptidase cleavage, and enhanced IgG binding properties by preorganization, potentially reducing conformational entropy loss upon binding. In this work, a Z domain trimer (Z3) was cyclized using protein intein splicing. Interactions of cyclic and linear Z3 with human IgG₁ were characterized by differential scanning fluorimetry (DSF), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC). DSF showed a 5 ℃ increase in IgG₁ melting temperature when bound by each Z3 variant. SPR showed the dissociation constants of linear and cyclized Z3 with IgG₁ to be 2.9 nM and 3.3 nM, respectively. ITC gave association enthalpies for linear and cyclic Z3 with IgG₁ of −33.0 kcal/mol and −32.7 kcal/mol, and −T∆S of association 21.2 kcal/mol and 21.6 kcal/mol, respectively. The compact cyclic Z3 protein contains 2 functional binding sites and exhibits carboxypeptidase Y-resistance. The results suggest cyclization as a potential approach toward more stable SpA-based affinity ligands, and this analysis may advance our understanding of protein engineering for ligand and drug development. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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24 pages, 5313 KiB

Open AccessArticle

Evolutionary Divergence of Phosphorylation to Regulate Interactive Protein Networks in Lower and Higher Species

by Claude Pasquier and Alain Robichon

Int. J. Mol. Sci. 2022, 23(22), 14429; https://doi.org/10.3390/ijms232214429 - 20 Nov 2022

Cited by 2 | Viewed by 1027

Abstract

The phosphorylation of proteins affects their functions in extensively documented circumstances. However, the role of phosphorylation in many interactive networks of proteins remains very elusive due to the experimental limits of exploring the transient interaction in a large complex of assembled proteins induced by stimulation. Previous studies have suggested that phosphorylation is a recent evolutionary process that differently regulates ortholog proteins in numerous lineages of living organisms to create new functions. Despite the fact that numerous phospho-proteins have been compared between species, little is known about the organization of the full phospho-proteome, the role of phosphorylation to orchestrate large interactive networks of proteins, and the intertwined phospho-landscape in these networks. In this report, we aimed to investigate the acquired role of phosphate addition in the phenomenon of protein networking in different orders of living organisms. Our data highlighted the acquired status of phosphorylation in organizing large, connected assemblages in Homo sapiens. The protein networking guided by phosphorylation turned out to be prominent in humans, chaotic in yeast, and weak in flies. Furthermore, the molecular functions of GO annotation enrichment regulated by phosphorylation were found to be drastically different between flies, yeast, and humans, suggesting an evolutionary drift specific to each species. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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11 pages, 1239 KiB

Open AccessArticle

From Solution Studies of Pharmaceuticals (Aspirin and Related Compounds) to the Thermodynamics of Aspirin-β-Cyclodextrin Interaction in water and N,N-Dimethylformamide

by Angela F. Danil de Namor, Alexandros Cambanis, Nawal Al Hakawati and Rasha Khalife

Int. J. Mol. Sci. 2022, 23(19), 11750; https://doi.org/10.3390/ijms231911750 - 04 Oct 2022

Cited by 1 | Viewed by 1379

Abstract

The solution behavior of pharmaceuticals (acetylsalicylic acid, 4-acetoxybenzoic acid and 5-acetylsalicylic acid) in water and N,N-Dimethylformamide (DMF) at 298.15 K were investigated through solubility, conductance and calorimetric measurements. Taking into account the formation of ion pairs of these pharmaceuticals in water, the solution Gibbs energies of the dissociated electrolytes in this solvent were calculated. Thus, the solution thermodynamics of these compounds in water are reported using enthalpy data obtained by calorimetry. These pharmaceuticals undergo solvation when exposed to a saturated atmosphere of DMF. As the composition of the solid is not the same as that in solution, the Gibbs energy of the solutions of these compounds could not be obtained; only enthalpy data are reported. The thermodynamics of the interaction of acetylsalicylic acid (aspirin) with β-cyclodextrin in water and DMF is fully discussed, emphasizing the two different processes that take place in water at the two different pHs. In all cases, the favorable Gibbs energies for these processes are entropically controlled, mainly resulting from the higher dehydration/desolvation that the receptor undergoes upon interaction with the guest. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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9 pages, 1453 KiB

Open AccessCommunication

AI-Based Protein Interaction Screening and Identification (AISID)

by Zheng-Qing Fu, Hansen L. Sha and Bingdong Sha

Int. J. Mol. Sci. 2022, 23(19), 11685; https://doi.org/10.3390/ijms231911685 - 02 Oct 2022

Viewed by 2353

Abstract

In this study, we presented an AISID method extending AlphaFold-Multimer’s success in structure prediction towards identifying specific protein interactions with an optimized AISIDscore. The method was tested to identify the binding proteins in 18 human TNFSF (Tumor Necrosis Factor superfamily) members for each of 27 human TNFRSF (TNF receptor superfamily) members. For each TNFRSF member, we ranked the AISIDscore among the 18 TNFSF members. The correct pairing resulted in the highest AISIDscore for 13 out of 24 TNFRSF members which have known interactions with TNFSF members. Out of the 33 correct pairing between TNFSF and TNFRSF members, 28 pairs could be found in the top five (including 25 pairs in the top three) seats in the AISIDscore ranking. Surprisingly, the specific interactions between TNFSF10 (TNF-related apoptosis-inducing ligand, TRAIL) and its decoy receptors DcR1 and DcR2 gave the highest AISIDscore in the list, while the structures of DcR1 and DcR2 are unknown. The data strongly suggests that AlphaFold-Multimer might be a useful computational screening tool to find novel specific protein bindings. This AISID method may have broad applications in protein biochemistry, extending the application of AlphaFold far beyond structure predictions. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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14 pages, 2958 KiB

Open AccessArticle

Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity

by Motonori Tsuji

Int. J. Mol. Sci. 2022, 23(19), 11009; https://doi.org/10.3390/ijms231911009 - 20 Sep 2022

Cited by 1 | Viewed by 2189

Abstract

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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17 pages, 3526 KiB

Open AccessArticle

Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8

by Sara Insausti, Miguel Garcia-Porras, Johana Torralba, Izaskun Morillo, Ander Ramos-Caballero, Igor de la Arada, Beatriz Apellaniz, Jose M. M. Caaveiro, Pablo Carravilla, Christian Eggeling, Edurne Rujas and Jose L. Nieva

Int. J. Mol. Sci. 2022, 23(18), 10767; https://doi.org/10.3390/ijms231810767 - 15 Sep 2022

Viewed by 2093

Abstract

Antibody engagement with the membrane-proximal external region (MPER) of the envelope glycoprotein (Env) of HIV-1 constitutes a distinctive molecular recognition phenomenon, the full appreciation of which is crucial for understanding the mechanisms that underlie the broad neutralization of the virus. Recognition of the HIV-1 Env antigen seems to depend on two specific features developed by antibodies with MPER specificity: (i) a large cavity at the antigen-binding site that holds the epitope amphipathic helix; and (ii) a membrane-accommodating Fab surface that engages with viral phospholipids. Thus, besides the main Fab–peptide interaction, molecular recognition of MPER depends on semi-specific (electrostatic and hydrophobic) interactions with membranes and, reportedly, on specific binding to the phospholipid head groups. Here, based on available cryo-EM structures of Fab–Env complexes of the anti-MPER antibody 10E8, we sought to delineate the functional antibody–membrane interface using as the defining criterion the neutralization potency and binding affinity improvements induced by Arg substitutions. This rational, Arg-based mutagenesis strategy revealed the position-dependent contribution of electrostatic interactions upon inclusion of Arg-s at the CDR1, CDR2 or FR3 of the Fab light chain. Moreover, the contribution of the most effective Arg-s increased the potency enhancement induced by inclusion of a hydrophobic-at-interface Phe at position 100c of the heavy chain CDR3. In combination, the potency and affinity improvements by Arg residues delineated a protein–membrane interaction site, whose surface and position support a possible mechanism of action for 10E8-induced neutralization. Functional delineation of membrane-interacting patches could open new lines of research to optimize antibodies of therapeutic interest that target integral membrane epitopes. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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16 pages, 8974 KiB

Open AccessArticle

Unveiling the Essential Role of Arkadia’s Non-RING Elements in the Ubiquitination Process

by Maria Birkou, Georgia N. Delegkou, Konstantinos D. Marousis, Nefeli Fragkaki, Tamara Toro, Vasso Episkopou and Georgios A. Spyroulias

Int. J. Mol. Sci. 2022, 23(18), 10585; https://doi.org/10.3390/ijms231810585 - 13 Sep 2022

Cited by 2 | Viewed by 1481

Abstract

Arkadia is a positive regulator of the TGFβ-SMAD2/3 pathway, acting through its C-terminal RING-H2 domain and targeting for degradation of its negative regulators. Here we explore the role of regions outside the RING domain (non-RING elements) of Arkadia on the E2-E3 interaction. The contribution of the non-RING elements was addressed using Arkadia RING 68 aa and Arkadia 119 aa polypeptides. The highly conserved NRGA (asparagine-arginine-glycine-alanine) and TIER (threonine-isoleucine-glutamine-arginine) motifs within the 119 aa Arkadia polypeptide, have been shown to be required for pSMAD2/3 substrate recognition and ubiquitination in vivo. However, the role of the NRGA and TIER motifs in the enzymatic activity of Arkadia has not been addressed. Here, nuclear magnetic resonance interaction studies with the E2 enzyme, UBCH5B, C85S UBCH5B-Ub oxyester hydrolysis, and auto-ubiquitination assays were used to address the role of the non-RING elements in E2-E3 interaction and in the enzymatic activity of the RING. The results support that the non-RING elements including the NRGA and TIER motifs are required for E2-E3 recognition and interaction and for efficient auto-ubiquitination. Furthermore, while Arkadia isoform-2 and its close homologue Arkadia 2C are known to interact with free ubiquitin, the results here showed that Arkadia isoform-1 does not interact with free ubiquitin. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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25 pages, 5396 KiB

Open AccessArticle

Structural and Functional Insights into CP2c Transcription Factor Complexes

by Seung Han Son, Min Young Kim, Eunbi Jo, Vladimir N. Uversky and Chul Geun Kim

Int. J. Mol. Sci. 2022, 23(12), 6369; https://doi.org/10.3390/ijms23126369 - 07 Jun 2022

Cited by 4 | Viewed by 1505

Abstract

CP2c, also known as TFCP2, α-CP2, LSF, and LBP-1c, is a prototypic member of the transcription factor (TF) CP2 subfamily involved in diverse ubiquitous and tissue/stage-specific cellular processes and in human malignancies including cancer. Despite its importance, many fundamental regulatory mechanisms of CP2c are still unclear. Here, we uncover unprecedented structural and functional aspects of CP2c using DSP crosslinking and Western blot in addition to conventional methods. We found that a monomeric form of a CP2c homotetramer (tCP2c; [C4]) binds to the known CP2c-binding DNA motif (CNRG-N(5~6)-CNRG), whereas a dimeric form of a CP2c, CP2b, and PIAS1 heterohexamer ([C2B2P2]₂) binds to the three consecutive CP2c half-sites or two staggered CP2c binding motifs, where the [C4] exerts a pioneering function for recruiting the [C2B2P2]₂ to the target. All CP2c exists as a [C4], or as a [C2B2P2]₂ or [C2B2P2]₄ in the nucleus. Importantly, one additional cytosolic heterotetrameric CP2c and CP2a complex, ([C2A2]), exerts some homeostatic regulation of the nuclear complexes. These data indicate that these findings are essential for the transcriptional regulation of CP2c in cells within relevant timescales, providing clues not only for the transcriptional regulation mechanism by CP2c but also for future therapeutics targeting CP2c function. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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14 pages, 3326 KiB

Open AccessArticle

Study on the Preparation of Estrone Molecularly Imprinted Polymers and Their Application in a Quartz Crystal Microbalance Sensor via a Computer-Assisted Design

by Jin Liu, Xuhong Cai, Junbo Liu, Dadong Liang, Kaiyin Chen, Shanshan Tang and Bao Xu

Int. J. Mol. Sci. 2022, 23(10), 5758; https://doi.org/10.3390/ijms23105758 - 20 May 2022

Cited by 3 | Viewed by 1205

Abstract

Computer simulations are widely used for the selection of conditions for the synthesis of molecularly imprinted polymers and can rapidly reduce the experimental cycle time and save labor and materials. In this paper, estrone molecularly imprinted polymers (E1-MIPs) are designed at the M062X/6-311+G(d,p) level with itaconic acid (IA) as the functional monomer. The imprinted molar ratio between E1 and IA was optimized, cross-linkers and solvents were screened, and the nature of interactions between E1 and IA was explored. The simulated results showed that pentaerythritol triacrylate was the best cross-linker. Meanwhile, when the imprinted molar ratio between E1 and IA was 1:4, the E1–IA complex had the largest amount of hydrogen bonds, the lowest binding energy, and the strongest stability. Using the simulation results as guidance, the E1-MIPs were prepared to modify the electrons of a quartz crystal microbalance (QCM) sensor. The experimental studies showed that the E1-MIPs-QCM sensor had the highest adsorption capacity to E1 in comparison with their analogues, and the lowest detection value of the sensor was 16.00 μg/L. The computer simulations and experimental studies could provide guidance for synthesize novel E1-MIPs materials. It also could provide important references and directions for the application of E1-MIPs. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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Review

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13 pages, 9045 KiB

Open AccessReview

Successes and Failures of Static Aptamer-Target 3D Docking Models

by John G. Bruno

Int. J. Mol. Sci. 2022, 23(22), 14410; https://doi.org/10.3390/ijms232214410 - 19 Nov 2022

Cited by 3 | Viewed by 1762

Abstract

While Molecular Dynamics simulation programs are probably superior for predicting the binding and affinity of aptamers and their cognate ligands, such molecular dynamics programs require more computing power and analysis time than static docking programs that are more widely accessible to the scientific community on the internet. Static docking programs can be used to investigate the geometric fit of rigid DNA or RNA aptamer 3D structures and their ligands to aid in predicting the relative affinities and cross-reactivity of various potential ligands. Herein, the author describes when such static 3D docking analysis has worked well to produce useful predictions or confirmation of high-affinity aptamer interactions or successful aptamer beacon behavior and when it has not worked well. The analysis of why failures may occur with static 3D computer models is also discussed. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular Recognition II)

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