Investigations into Protein Structure: 2nd Edition

A Special Issue of Biophysica (ISSN 2673-4125).

Deadline for manuscript submissions: 31 October 2026 | Viewed by 3030

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Special Issue Information

Dear Colleagues,

Proteins, as the fundamental components of life, are not just essential to the complex interplay of cellular, physiological, and immunological processes, but are, in fact, the ultimate expression of genetic information, meticulously decoded from DNA. Within the dynamic environment of the cell, proteins perform a wide range of functions, acting as both structural frameworks and catalysts that power biological reactions. A sophisticated code embedded in the four-letter DNA alphabet is central to their versatility. This genetic code, through sequences of amino acids, determines the folding and configuration of proteins into an astounding variety of structures, each uniquely suited to a specific role. From the resilient collagen fibers that provide tissue support to the dynamic molecular motors enabling cellular motion, proteins exemplify the diversity encoded in the genome.

Additionally, proteins orchestrate biochemical reactions and can serve as antigens, sparking targeted immune responses and therapeutic innovations. Their amino acid sequences and specific regions act as catalysts, mediate protein–protein interactions, and drive numerous biological processes that would otherwise proceed sluggishly. Whether functioning as enzymes facilitating nutrient breakdown for energy or as signaling molecules regulating cellular communication, proteins are not just important—they are central to all biological activity. Despite their complexity, proteins arise from a relatively simple genetic blueprint that can produce an almost limitless array of structures, each optimized for its function. This simplicity amidst complexity highlights the elegance of life’s molecular machinery, driven by the hierarchical structures of proteins. From providing structural support to ensuring catalytic efficiency, proteins embody the adaptability and precision of biological systems, highlighting life's extraordinary intricacies. This Special Issue aims to gather studies that push the boundaries of our understanding of protein structures, including enzymes, structural proteins, membranes, and other components of living organisms. Contributions related to bioinformatics, methodologies for examining the four structural levels of proteins, SAXS, cryoelectron microscopy, the interactions between these levels and biochemical and immunological properties, and drug development studies are particularly encouraged. Alongside the wealth of knowledge that has been accumulated over time, this comprehensive collection of expert articles on this topic will provide significant value to researchers worldwide.

Prof. Dr. Salvatore Giovanni De Simone
Guest Editor

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Keywords

  • protein structure
  • enzymes
  • structural proteins
  • membranes

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Published Papers (2 papers)

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20 pages, 2483 KB  
Protocol
Amber Suppressor tRNA-Based Mutagenesis for Positional Semi-Saturated Mutagenesis with Natural Amino Acid Substitutions: An Approach for Mapping Positional Contributions to Protein Function
by Pierce T. O’Neil, Tonya N. Zeczycki, Kyung-Tae Park, Mykola V. Rodnin, Liskin Swint-Kruse, Renaud Vincentelli and Aron W. Fenton
Biophysica 2026, 6(4), 72; https://doi.org/10.3390/biophysica6040072 - 10 Aug 2026
Viewed by 511
Abstract
There is a growing interest in methods that illuminate the contributions of individual positions to a protein’s function by site-saturating mutagenesis. However, a commonly used approach for assessing variant libraries with deep mutational scanning relies on readouts of biological fitness, which is influenced [...] Read more.
There is a growing interest in methods that illuminate the contributions of individual positions to a protein’s function by site-saturating mutagenesis. However, a commonly used approach for assessing variant libraries with deep mutational scanning relies on readouts of biological fitness, which is influenced by many protein properties (ligand binding, catalysis, allosteric effector binding, allosteric coupling between effector and substrate, etc.). Biochemical assays are required to distinguish among these factors. To facilitate the generation and biochemical evaluation of the functions of large numbers of substituted positions, we co-express updated plasmids coding a series of amber suppressor tRNA in a high-throughput workflow; these plasmids are available at Addgene. As an example, our goal is to evaluate whether allosteric mechanisms are conserved among homologs. Because homologs often have <50% identity, and up to 30% of a protein’s positions can contribute to allosteric function, we reason that the set of “allosteric” positions likely differs among homologs. Our high-throughput workflow includes the following steps: Step (1) an amber suppressor tRNA-based mutagenesis protocol; Step (2) a robotic system for protein expression/purification and functional assays; and Step (3) a method for aggregating results from multiple substitutions at each position into a composite score. Full article
(This article belongs to the Special Issue Investigations into Protein Structure: 2nd Edition)
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11 pages, 950 KB  
Hypothesis
Decoding How Proteins Fold
by Jorge A. Vila
Biophysica 2026, 6(2), 36; https://doi.org/10.3390/biophysica6020036 - 21 Apr 2026
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Abstract
One of the most puzzling and unsolved challenges in molecular biology is understanding how proteins fold. Despite having advanced predictive tools that can accurately estimate the native structures of proteins, we still lack a comprehensive model that explains how amino acid sequences dictate [...] Read more.
One of the most puzzling and unsolved challenges in molecular biology is understanding how proteins fold. Despite having advanced predictive tools that can accurately estimate the native structures of proteins, we still lack a comprehensive model that explains how amino acid sequences dictate folding pathways and trajectories. This manuscript introduces a novel treatment for the issue by employing the “principle of least action.” This approach enables us to explore an intriguing question: how does a protein achieve its native state at a constant folding rate and within a biologically plausible time frame? A response to this inquiry will help us understand why proteins must fold along specific pathways and identify the boundary conditions that limit their availability. Furthermore, the principle of least action—together with the effective trajectory conjecture—enables us to explain why different proteins could exhibit the same folding rate. Finally, it will enable us to provide an in-depth description of the genesis and solution of Levinthal’s paradox. Our results are expected to pave the way for a more profound understanding of how proteins fold, shedding light on how the amino acid sequence and its surrounding environment encode the protein’s folding pathways and, consequently, the protein’s three-dimensional structure. Full article
(This article belongs to the Special Issue Investigations into Protein Structure: 2nd Edition)
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