Proteins-Structure Function and Bioinformatics最新文献

{"title":"Ligand Binding Prediction on Pharmaceutical and Nucleic Acid Targets by the CoDock Group in CASP16.","authors":"Ren Kong, Zunyun Jiang, Xufeng Lu, Liangxu Xie, Shan Chang","doi":"10.1002/prot.70032","DOIUrl":"https://doi.org/10.1002/prot.70032","url":null,"abstract":"<p><p>Ligand binding prediction is a critical component of structure-based drug design, gaining prominence in Critical Assessment of protein Structure Prediction (CASP) since its introduction in CASP15. In CASP16, the challenges expanded to include protein-ligand and nucleic acid-ligand binding predictions, alongside binding affinity ranking, posing greater computational and methodological demands. This study presents a sophisticated prediction strategy combining template-based docking, multiple receptor conformations, and AI-driven scoring to address these challenges. For protein-ligand systems (L1000-L4000), we leveraged structural templates from PDB, ligand similarity analysis, and tools like CoDock-Ligand and AutoDock Vina to predict binding poses. Key successes included accurate predictions for targets like SARS-CoV-2 Mpro (L4000) and Autotaxin (L3000), though challenges persisted with binding site flexibility and pose ranking. The prediction of ligand pose achieved satisfactory results, with more than 66% of the distribution having RMSD less than 3 Å. Nucleic acid-ligand predictions (e.g., ZTP riboswitch) yielded mixed results, highlighting limitations in RNA/DNA structural accuracy. Affinity prediction employed diverse methods, with machine learning-based SVR_Conjoint outperforming physics-based approaches (Kendall's Tau = 0.43). Our strategy demonstrated robustness in CASP16, yet underscored the need for advancements in handling conformational dynamics and scoring accuracy. This work provides a framework for future ligand binding prediction efforts in computational drug discovery.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics.","authors":"Sharif Arar, Md Anzarul Haque, Rakez Kayed","doi":"10.1002/prot.26561","DOIUrl":"10.1002/prot.26561","url":null,"abstract":"<p><p>Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to the soluble amyloid-β protofibrils, all the treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling to find a breakthrough in AD therapeutic medicine, which is partially attributable to lack in understanding of the structural information associated with the intrinsically disordered proteins and amyloids. One of the major challenges in this area of research is to understand the structural diversity of intrinsically disordered proteins under in vitro conditions. Therefore, in this review, we have summarized the in vitro applications of biophysical methods, which are aimed to shed some light on the heterogeneity, pathogenicity, structures and mechanisms of the intrinsically disordered protein aggregates associated with proteinopathies including AD. This review will also rationalize some of the strategies in modulating disease-relevant pathogenic protein entities by small molecules using structural biology approaches and biophysical characterization. We have also highlighted tools and techniques to simulate the in vivo conditions for native and cytotoxic tau/amyloids assemblies, urge new chemical approaches to replicate tau/amyloids assemblies similar to those in vivo conditions, in addition to designing novel potential drugs.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1314-1329"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10834863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10130277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient and accurate binding free energy calculation of Aβ_9-40 protofilament propagation.","authors":"Christina V Frost, Nadine Schwierz, Martin Zacharias","doi":"10.1002/prot.26683","DOIUrl":"10.1002/prot.26683","url":null,"abstract":"<p><p>Self-assembled aggregation of peptides and proteins into regular amyloid fibrils is associated with several neurodegenerative diseases. In case of Alzheimer's disease proteolytic cleavage products of the amyloid precursor protein form pathological amyloid-beta fibrils in a nucleation and propagation phase. The molecular details and thermodynamic driving forces of amyloid formation are not well understood, but are of high relevance for potential pharmacological interference. We used atomistic binding free energy simulations to calculate the free energy of protofilament propagation by an additional Aβ_9-40 peptide binding to the protofilament tip. It requires sampling of relevant conformational transitions which is challenging since the monomeric Aβ_9-40 peptide is intrinsically disordered. However, the convergence of umbrella simulations can be enhanced by applying additional restraining potentials on the axial, orientational and conformational degrees of freedom. The improved convergence leads to a much closer agreement with experimental binding free energy data compared to unrestrained umbrella sampling. Moreover, the restraining approach results in a separation of contributions to the total binding free energy. The calculated contributions indicate that the free energy change associated with the restriction of conformational freedom upon propagation makes a large opposing contribution of higher magnitude than the total binding free energy. Finally, optimization of the approach leads to further significant reduction of the computational demand which is crucial for systematic studies on mutations, denaturants and inhibitors in the fibril propagation step.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1393-1408"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140121485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.","authors":"Madison K Kuhn, Elizabeth A Proctor","doi":"10.1002/prot.26723","DOIUrl":"10.1002/prot.26723","url":null,"abstract":"<p><p>Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1330-1348"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-protein association properties of human βB2-crystallins.","authors":"José-Luis Velasco-Bolom, Laura Domínguez","doi":"10.1002/prot.26547","DOIUrl":"10.1002/prot.26547","url":null,"abstract":"<p><p>Protein-protein association events are involved in many physiological and pathological processes. Cataract disease is a pathology that manifests protein aggregation of crystallins. β-Crystallins are present in a high proportion in the eye lens. Therefore, the structural study of the dimerization properties of crystallins can shed light on the first stages of protein aggregation. In the present work, we examine the protein-protein association profiles of the human βB2-crystallin by employing extensive coarse-grained molecular dynamics (CG-MD) and the Markov state analysis. Interestingly, our results clearly show important changes in the protein dimerization kinetics between wt-HβB2C and the deamidated systems. The two systems show dimeric conformations. However, the association and dissociation rates are very different. Our results show that the deamidated system can associate faster and dissociate slower than the wt- HβB2C. The deamidated system is in a slightly opened conformation with the Greek-key motifs well folded, suggesting that a complete unfolding of the protein is not required for aggregation. Our results describe the first stages of crystallin aggregation due to post-translational modifications.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1361-1368"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9783893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure Modeling Protocols for Protein Multimer and RNA in CASP16 With Enhanced MSAs, Model Ranking, and Deep Learning.","authors":"Yuki Kagaya, Tsukasa Nakamura, Jacob Verburgt, Anika Jain, Genki Terashi, Pranav Punuru, Emilia Tugolukova, Joon Hong Park, Anouka Saha, David Huang, Daisuke Kihara","doi":"10.1002/prot.70033","DOIUrl":"10.1002/prot.70033","url":null,"abstract":"<p><p>We present the methods and results of our protein complex and RNA structure predictions at CASP16. Our approach integrated multiple state-of-the-art deep learning models with a consensus-based scoring method. To enhance the depth of multiple sequence alignments (MSAs), we employed a large metagenomic sequence database. Model ranking was performed with a state-of-the-art consensus ranking method, to which we added more scoring terms. These predictions were further refined manually based on literature evidence. For RNA, we adopted an ensemble approach that incorporated multiple state-of-the-art methods, centered around our NuFold framework. As a result, our KiharaLab group ranked first in protein complex prediction and third in RNA structure prediction. A detailed analysis of targets that significantly differed from those of other groups highlighted both the strengths of our MSA and scoring strategies, as well as areas requiring further improvement.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metastable alpha-rich and beta-rich conformations of small Aβ42 peptide oligomers.","authors":"Phuong H Nguyen, Fabio Sterpone, Philippe Derreumaux","doi":"10.1002/prot.26495","DOIUrl":"10.1002/prot.26495","url":null,"abstract":"<p><p>Probing the structures of amyloid-β (Aβ) peptides in the early steps of aggregation is extremely difficult experimentally and computationally. Yet, this knowledge is extremely important as small oligomers are the most toxic species. Experiments and simulations on Aβ42 monomer point to random coil conformations with either transient helical or β-strand content. Our current conformational description of small Aβ42 oligomers is funneled toward amorphous aggregates with some β-sheet content and rare high energy states with well-ordered assemblies of β-sheets. In this study, we emphasize another view based on metastable α-helix bundle oligomers spanning the C-terminal residues, which are predicted by the machine-learning AlphaFold2 method and supported indirectly by low-resolution experimental data on many amyloid polypeptides. This finding has consequences in developing novel chemical tools and to design potential therapies to reduce aggregation and toxicity.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1308-1313"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9273329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical micellar concentration determination of pure phospholipids and lipid-raft and their mixtures with cholesterol.","authors":"Sofia Serravalle, Martina Pisano, Michele F M Sciacca, Nancy Salamone, Luciano Sicali, Giuseppe Mazzara, Luca Costa, Carmelo La Rosa","doi":"10.1002/prot.26669","DOIUrl":"10.1002/prot.26669","url":null,"abstract":"<p><p>Phospholipids in biological membranes establish a chemical equilibrium between free phospholipids in the aqueous phase (CMC) and self-assembled phospholipids in vesicles, keeping the CMC constant. The CMC is different for each phospholipid, depends on the amount of cholesterol, and, according to the lipid-chaperone hypothesis, controls the interaction between free phospholipids and amyloidogenic proteins (such as amylin, amyloid-β, and α-synuclein, all of which are, respectively, associated with a different proteinopathy), which governs the formation of a toxic complex between free lipids and proteins that leads to membrane destruction. Here, we provide quantitative measurements of CMCs and bilayer stability of pure phospholipids, lipid rafts, and their mixture with cholesterol by fluorescence methods (using pyrene as a probe) and light scattering techniques (resonance Rayleigh scattering and fixed-angle light scattering) performed on LUVs, as well as AFM to measure LUV dimensions. Also, we test the lipid-chaperone hypothesis on human IAPP interacting with different mixture of POPC cholesterol. Stated the importance of CMC in membrane stability and protein aggregation processes, these results could be a starting point for the development of a quantitative kinetic model for the lipid chaperone hypothesis.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1383-1392"},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139486481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationalizing Enhanced Affinity of Engineered T-Cell Receptors in Cancer Immunotherapy Through Interaction Energy Calculations and Residue Correlation Analysis.","authors":"Mario Frezzini, Daniele Narzi","doi":"10.1002/prot.70028","DOIUrl":"https://doi.org/10.1002/prot.70028","url":null,"abstract":"<p><p>The advancement of T cell engineering has significantly transformed the field of cancer immunotherapy. In particular, T cells equipped with modified T cell receptors present a promising therapeutic strategy, especially for addressing solid tumors. Nonetheless, critical obstacles, including suboptimal clinical response rates, off-target toxicity, and the immunosuppressive nature of the tumor microenvironment, have impeded the full clinical implementation of this approach. Understanding the molecular determinants governing the interaction between T-cell receptors and major histocompatibility complex molecules is pivotal not only for designing TCRs capable of selectively and effectively recognizing MHC on cancer cells but also for minimizing off-target toxicity, thereby improving the safety profile of TCR-based therapies. In this study, we used a test case involving a natural TCR (c728) and its affinity-enhanced variant (c796), which differ by a single conservative mutation in the <math> <semantics><mrow><mi>β</mi> <mspace></mspace> <mtext>CDR1</mtext></mrow> <annotation>$$ beta mathrm{CDR}1 $$</annotation></semantics> </math> region. Through molecular dynamics simulations, MM/PBSA binding energy and Free Energy Perturbation calculations, residue-specific energy decomposition, and correlation analyses, we dissected the molecular basis of the engineered TCR's six-fold increase in binding affinity for the peptide-MHC complex compared to its parental counterpart. Interestingly, our results indicate that this affinity enhancement is not directly attributable to the mutation itself but rather to the dynamic interplay of both proximal and distal residues that are either directly correlated with the mutation or connected via allosteric pathways. Our findings, which align with experimental data, highlight the nuanced role of structural flexibility and allosteric communication in shaping TCR-pMHC interactions. By demonstrating the utility of combining computational techniques to unravel these dynamics, this work emphasizes how similar approaches can guide the rational design of engineered TCRs with improved efficacy and specificity, advancing their application in cancer immunotherapy.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering Sequence and Structural Characteristics of Fungal Expansin-Related Proteins With Potential to Drive Substrate Targeting.","authors":"Anna Pohto, Taru Koitto, Deepika Dahiya, Alessandra Castro, Elizaveta Sidorova, Martina Huusela, Scott E Baker, Adrian Tsang, Emma Master","doi":"10.1002/prot.70029","DOIUrl":"https://doi.org/10.1002/prot.70029","url":null,"abstract":"<p><p>Expansins loosen plant cell wall networks through disrupting non-covalent bonds between cellulose microfibrils and matrix polysaccharides. Whereas expansins were first discovered in plants, expansin-related proteins have since been identified in bacteria and fungi. The biological function of microbial expansins remains unclear; however, several studies have shown distinct binding preferences toward different structural polysaccharides. Earlier studies of bacterial expansin-related proteins uncovered sequence and structural features that correlate to substrate binding. Herein, 20 fungal expansin-related sequences were recombinantly produced in Komagataella phaffii, and the purified proteins were compared in terms of substrate binding to cellulosic and chitinous substrates. The impact of pH on the zeta potential of prioritized substrates was also measured, and Principal Component Analysis was performed to uncover correlations between protein characteristics (e.g., pI, hydrophobicity, surface charge distribution) and measured substrate binding preferences. Whereas acidic proteins with a predicted pI less than 5.0 preferentially bound to chitin, basic proteins with pI greater than 8.0 preferentially bound to xylan and xylan-containing fiber. Similar to many cellulases, binding to cellulose was correlated to relatively high aromatic amino acid content in the protein sequence and presence of a carbohydrate binding module (CBM), which in the case of expansins is a C-terminal CBM63. Whereas overall sequence characteristics could be correlated to substrate binding preference, the identity of amino acids occupying conserved positions that impact protein activity was better correlated with loosenin versus expansin classifications.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}