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Biomolecules
Special Issues
Protein Biophysics
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Protein Biophysics

A Special Issue of Biomolecules (ISSN 2218-273X) belonging to the section "Molecular Biophysics: Structure, Dynamics, and Function".

Deadline for manuscript submissions: 31 May 2027 | Viewed by 10853

Editors

Prof. Dr. Vladimir N. Uversky

grade E-Mail Website
Guest Editor
Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Interests: protein structure; protein folding; protein misfolding; intrinsically disordered proteins; conformational disease; partially folded protein; folding intermediate; protein aggregation
Special Issues, Collections and Topics in MDPI journals
Dr. Orkid Coskuner-Weber

E-Mail Website
Guest Editor
Molecular Biotehnology, Turkish-German University, Beykoz, Turkey
Interests: intrinsically disordered proteins and bio-inspired polymers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins are complex and versatile biological macromolecules with a myriad of structures and countless functions. Order and disorder are intricately intertwined in proteins, with many proteins being known to fold into unique structures in order to gain important functions, and with functions of many other proteins being dependent on the absence of unique structure and related ability to undergo disorder-to-order or order-to-disorder functional transitions. Being interaction specialists, proteins can act alone or require various partners for their functionality. They can assemble into highly specific proteinacous machines with sophisticated geometry or form liquid-like droplets. They can control and regulate countless biological processes, and, in turn, are tightly controlled and regulated themselves by a broad variety of cellular mechanisms. All this highlights the close link between protein science and different fields of molecular biophysics. This Special Issue entitled “Protein Biophysics” aims to collect high-quality research articles, short communications, and review articles in all fields of protein biophysics. We encourage scholars in related fields to contribute papers reflecting the latest progress in their research fields.

Topics of this Special Issue include, but are not limited to, the following:

  • Protein biophysics;
  • Protein engineering;
  • Protein folding;
  • Protein function;
  • Protein misfolding;
  • Protein stability;
  • Protein structure and prediction;
  • Protein structural and conformational dynamics;
  • Posttranslational modifications;
  • Peptide and protein aggregation;
  • Pathogenesis of proteinopathies;
  • Intrinsically disordered proteins;
  • Protein–ligand interactions;
  • Protein–protein interactions;
  • Protein–nucleic acid interactions;
  • Membrane proteins;
  • Liquid–liquid phase separation;
  • Biosensing, spectroscopy, and microfluidics;
  • Kinetics and thermodynamics;
  • Applications in biotechnology and bioengineering.

Prof. Dr. Vladimir N. Uversky
Dr. Orkid Coskuner-Weber
Guest Editors

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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules 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

  • protein function
  • protein folding
  • protein misfolding
  • protein structure
  • protein dynamics
  • protein stability
  • protein and peptide aggregation
  • posttranslational modifications
  • intrinsically disordered proteins
  • protein–ligand interactions
  • protein–protein interactions
  • protein–nucleic acid interactions
  • membrane proteins
  • liquid–liquid phase separation

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (6 papers)

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Research

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17 pages, 11615 KB  
Article
Structural and Functional Interrogation of Active Streptococcus pneumoniae Sortase A
by Eunjeong Lee, Blaine Hunter Gordon, Jasmina S. Redzic, Anthony J. Saviola, Sean P. Maroney, Steven Shaw, Mila Cordero, Shaun Bevers, Angelo D’Alessandro, Kirk C. Hansen, Sarah E. Clark and Elan Eisenmesser
Biomolecules 2026, 16(9), 1231; https://doi.org/10.3390/biom16091231 - 25 Aug 2026
Viewed by 315
Abstract
Sortase A (SrtA) enzymes covalently anchor surface proteins to Gram-positive bacterial cell walls, promoting colonization and virulence. In Streptococcus pneumoniae, previous studies identified both a domain-swapped dimer and an active refolded monomer, but the active enzyme has not been characterized at the [...] Read more.
Sortase A (SrtA) enzymes covalently anchor surface proteins to Gram-positive bacterial cell walls, promoting colonization and virulence. In Streptococcus pneumoniae, previous studies identified both a domain-swapped dimer and an active refolded monomer, but the active enzyme has not been characterized at the structural and residue-specific level. Here, we performed quantitative proteomic comparisons of wild-type and SrtA knockout strains that confirmed the loss of multiple LPxTG-containing virulence factors, including ZmpB, NanA, and IgA1 protease, consistent with an essential role for SrtA in surface protein anchoring. To enable mechanistic studies, we established a biochemical framework to produce monomeric Streptococcus pneumoniae SrtA by refolding and developed a gel-based assay using recombinant substrates to monitor catalytic activity. The refolded monomer, but not the swapped dimer, catalyzed cleavage and transpeptidation of a canonical LPxTG substrate in a metal-independent manner under the conditions examined. We further report high-resolution NMR backbone assignments for the active monomer and identify substrate-induced chemical shift perturbations that localize to the active site. Together, these findings provide an integrated proteomic, biochemical, and NMR characterization of monomeric, catalytically active Streptococcus pneumoniae SrtA and reveal residue-specific interactions with a canonical LPNTG recognition peptide. Full article
(This article belongs to the Special Issue Protein Biophysics)
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16 pages, 1374 KB  
Article
Multimodal Anion-Exchange Resins for Chromatographic Separation of Antibody Aggregates
by Simona Kotuličová, Tomáš Molnár and Milan Polakovič
Biomolecules 2026, 16(6), 785; https://doi.org/10.3390/biom16060785 - 27 May 2026
Viewed by 667
Abstract
Efficient protein aggregate removal remains a major challenge in downstream bioprocessing because high aggregate clearance must be achieved without compromising monomer yield. Mixed-mode chromatography (MMC) has emerged as a promising approach, offering enhanced selectivity through combined ionic and hydrophobic interactions and salt-tolerant behavior. [...] Read more.
Efficient protein aggregate removal remains a major challenge in downstream bioprocessing because high aggregate clearance must be achieved without compromising monomer yield. Mixed-mode chromatography (MMC) has emerged as a promising approach, offering enhanced selectivity through combined ionic and hydrophobic interactions and salt-tolerant behavior. However, the relative roles of matrix pore accessibility and ligand density remain insufficiently understood. In this study, MMC adsorbents based on 4% and 6% agarose matrices were functionalized with a BMEA ligand. Inverse size-exclusion chromatography revealed that functionalization caused matrix syneresis, increasing dry matter content to 23% and enhancing mechanical rigidity. MMC-Ag4, with a larger mean pore radius (19.1 nm), exhibited a selectivity factor of 2 toward aggregates in static binding experiments, whereas the denser MMC-Ag6 (15.7 nm) showed no selectivity. In column studies using a feed containing 10% aggregates, MMC-Ag4 outperformed the commercial benchmark Capto Adhere, achieving monomer yields of 80–90% at 97–98% purity with salt tolerance up to 300 mM NaCl. These findings indicate that while MMC-Ag6 is limited by pore blockage, the optimized pore accessibility of MMC-Ag4 enables effective aggregate recognition. In conclusion, multimodal adsorbent design must balance ligand density with matrix porosity to ensure high resolution and yield in aggregate removal. Full article
(This article belongs to the Special Issue Protein Biophysics)
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26 pages, 6015 KB  
Article
Definition and Discovery of Tandem SH3-Binding Motifs Interacting with Members of the p47phox-Related Protein Family
by Zsofia E. Kalman, Tamas Lazar, Laszlo Dobson and Rita Pancsa
Biomolecules 2025, 15(12), 1641; https://doi.org/10.3390/biom15121641 - 22 Nov 2025
Viewed by 1677
Abstract
SH3 domains are widespread protein modules that mostly bind to proline-rich short linear motifs (SLiMs). Most known SH3 domain-motif interactions and canonical or non-canonical recognition specificities are described for individual SH3 domains. Although cooperation and coordinated motif binding between tandem SH3 domains has [...] Read more.
SH3 domains are widespread protein modules that mostly bind to proline-rich short linear motifs (SLiMs). Most known SH3 domain-motif interactions and canonical or non-canonical recognition specificities are described for individual SH3 domains. Although cooperation and coordinated motif binding between tandem SH3 domains has already been described for members of the p47phox-related protein family, individual cases have never been collected and analyzed collectively, which precluded the definition of the binding preferences and targeted discovery of further instances. Here, we apply an integrative approach that includes data collection, curation, bioinformatics analyses and state-of-the-art structure prediction methods to fill these gaps. A search of the human proteome with the sequence signatures of SH3 tandemization and follow-up structure analyses suggest that SH3 tandemization could be specific for this family. We define the optimal binding preference of tandemly arranged SH3 domains as [PAVIL]PPR[PR][^DE][^DE] and propose potential new instances of this SLiM among the family members and their binding partners. Structure predictions suggest the possibility of a novel, reverse binding mode for certain motif instances. In all, our comprehensive analysis of this unique SH3 binding mode enabled the identification of novel, interesting tandem SH3-binding motif candidates with potential therapeutic relevance. Full article
(This article belongs to the Special Issue Protein Biophysics)
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27 pages, 5073 KB  
Article
Activity of Serpins in Context to Hydrophobic Interaction
by Irena Roterman, Katarzyna Stapor, Grzegorz Zemanek, Dawid Dulak and Leszek Konieczny
Biomolecules 2025, 15(11), 1615; https://doi.org/10.3390/biom15111615 - 18 Nov 2025
Viewed by 900
Abstract
The activity of serpins uses a specific mechanism or process. This process comprises several steps and is related to significant structural changes that involve significant displacement of chain fragments and whole molecules of protease. An important role is played by a segment of [...] Read more.
The activity of serpins uses a specific mechanism or process. This process comprises several steps and is related to significant structural changes that involve significant displacement of chain fragments and whole molecules of protease. An important role is played by a segment of the serpin chain called the Reactive Central Loop (RCL), which interacts with the protease by inhibiting its activity. For the covalent binding of the protease to serpin, the movement of the protease molecule is an effect of splicing the RCL segment into beta-sheet A of serpin. There are structural forms—native, latent, Michaelis complex (non-covalent enzyme-inhibitor complex prior to RCL cleavage), covalent serpin–protease complex, and cleaved—associated with serpin activity. In this work, all these structural forms are discussed using the fuzzy oil drop (FOD-M) model, where the assessment criterion of structuring is based on identifying the type of hydrophobicity distribution. The analysis reveals the specificity of the inhibition mechanism, including the specific action of the RCL. The structural changes involved in this process have been shown to preserve the distribution of hydrophobicity in the form preferred by the aqueous environment in which serpins are active. The disorder (according to FOD-M model) in two complexes (Michaelis and covalent) is hypothetically treated as code for degradation factors. The applied model assesses the function-related structures using the hydrophobicity distribution as the criterion in contrast to many publications based on energetic aspects of serpin activity. Structural changes appear appropriate for water environments—the environment of serpin activity. Full article
(This article belongs to the Special Issue Protein Biophysics)
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28 pages, 4648 KB  
Article
Allosteric Control Overcomes Steric Limitations for Neutralizing Antibodies Targeting Conserved Binding Epitopes of the SARS-CoV-2 Spike Protein: Exploring the Intersection of Binding, Allostery, and Immune Escape with a Multimodal Computational Approach
by Mohammed Alshahrani, Vedant Parikh, Brandon Foley and Gennady Verkhivker
Biomolecules 2025, 15(9), 1340; https://doi.org/10.3390/biom15091340 - 18 Sep 2025
Cited by 2 | Viewed by 2261
Abstract
Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic [...] Read more.
Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate how these antibodies engage the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and influence its function. Our results reveal that neutralization efficacy arises from the interplay of direct interfacial interactions and allosteric effects. Group F1 antibodies (CR3022, EY6A, COVA1-16) primarily operate via classic allostery, modulating flexibility in RBD loop regions to indirectly interfere with the ACE2 receptor binding through long-range effects. Group F2 antibody DH1047 represents an intermediate mechanism, combining partial steric hindrance—through engagement of ACE2-critical residues T376, R408, V503, and Y508—with significant allosteric influence, facilitated by localized communication pathways linking the epitope to the receptor interface. Group F3 antibody S2X259 achieves potent neutralization through a synergistic mechanism involving direct competition with ACE2 and localized allosteric stabilization, albeit with potentially increased escape vulnerability. Dynamic network analysis identified a conserved “allosteric ring” within the RBD core that serves as a structural scaffold for long-range signal propagation, with antibody-specific extensions modulating communication to the ACE2 interface. These findings support a model where Class 4 neutralization strategies evolve through the refinement of peripheral allosteric connections rather than epitope redesign. This study establishes a robust computational framework for understanding the atomistic basis of neutralization activity and immune escape for Class 4 antibodies, highlighting how the interplay of binding energetics, conformational dynamics, and allosteric modulation governs their effectiveness against SARS-CoV-2. Full article
(This article belongs to the Special Issue Protein Biophysics)
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Review

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37 pages, 603 KB  
Review
Implicit Solvent Models and Their Applications in Biophysics
by Yusuf Bugra Severoglu, Betul Yuksel, Cagatay Sucu, Nese Aral, Vladimir N. Uversky and Orkid Coskuner-Weber
Biomolecules 2025, 15(9), 1218; https://doi.org/10.3390/biom15091218 - 23 Aug 2025
Cited by 8 | Viewed by 4020
Abstract
Solvents represent the quiet majority in biomolecular systems, yet modeling their influence with both speed and ri:gor remains a central challenge. This study maps the state of the art in implicit solvent theory and practice, spanning classical continuum electrostatics (PB/GB; DelPhi, APBS), modern [...] Read more.
Solvents represent the quiet majority in biomolecular systems, yet modeling their influence with both speed and ri:gor remains a central challenge. This study maps the state of the art in implicit solvent theory and practice, spanning classical continuum electrostatics (PB/GB; DelPhi, APBS), modern nonpolar and cavity/dispersion treatments, and quantum–continuum models (PCM, COSMO/COSMO-RS, SMx/SMD). We highlight where these methods excel and where they falter, namely, around ion specificity, heterogeneous interfaces, entropic effects, and parameter sensitivity. We then spotlight two fast-moving frontiers that raise both accuracy and throughput: machine learning-augmented approaches that serve as PB-accurate surrogates, learn solvent-averaged potentials for MD, or supply residual corrections to GB/PB baselines, and quantum-centric workflows that couple continuum solvation methods, such as IEF-PCM, to sampling on real quantum hardware, pointing toward realistic solution-phase electronic structures at emerging scales. Applications across protein–ligand binding, nucleic acids, and intrinsically disordered proteins illustrate how implicit models enable rapid hypothesis testing, large design sweeps, and long-time sampling. Our perspective argues for hybridization as a best practice, meaning continuum cores refined by improved physics, such as multipolar water, ML correctors with uncertainty quantification and active learning, and quantum–continuum modules for chemically demanding steps. Full article
(This article belongs to the Special Issue Protein Biophysics)
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