Biophysical chemistry最新文献

{"title":"Decoding SARS-CoV-2 variants: Mutations, viral stability, and breakthroughs in vaccines and therapies","authors":"Zainularifeen Abduljaleel","doi":"10.1016/j.bpc.2025.107413","DOIUrl":"10.1016/j.bpc.2025.107413","url":null,"abstract":"<div><div>This study investigates the infectivity of SARS-CoV-2 and its immune evasion mechanisms, particularly through mutations in the spike protein that enable the virus to escape host immune responses. As global vaccination efforts continue, understanding viral evolution and immune evasion strategies remains critical. This analysis focuses on fourteen key mutations (Arg346Lys, Lys417Asp, Leu452Glu, Leu452Arg, Phe456Leu, Ser477Asp, Thr478Lys, Glu484Ala, Glu484Lys, Glu484Gln, Gln493Arg, Gly496Ser, Glu498Arg, and His655Y) within the receptor-binding domain (RBD) of the spike protein. The results reveal consistent patterns of immune escape across various SARS-CoV-2 variants, with specific mutations influencing protein stability, binding affinity to the hACE2 receptor, and antibody recognition. These findings demonstrate how single-point mutations can destabilize the spike protein and reduce the efficacy of the immune response. By correlating expression levels and thermodynamic stability with immune evasion, this study provides valuable insights into the functional characteristics of the spike protein. The findings contribute to the understanding of immune escape variants and identify potential targets for enhancing vaccine efficacy and developing therapeutic approaches in response to the evolving SARS-CoV-2 landscape.</div></div><div><h3>Short summary</h3><div>The study investigates the infectivity of SARS-CoV-2 and its implications for immune evasion. It focuses on fourteen key mutations within the spike protein's Receptor-Binding Domain (S-RBD) and reveals consistent patterns associated with immune escape in various SARS-CoV-2 variants. The research highlights the influence of factors such as protein fold stability, hACE2 binding, and antibody evasion on spike protein evolution. Single-point immune escape variants alter virus stability, impacting antibody response success. The study provides valuable insights into immune escape variants and suggests avenues for enhancing vaccine efficacy. It also opens the way for novel therapeutic approaches in the context of SARS-CoV-2 variants.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107413"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photophysical and structural aspects of poly-L-tryptophan: π−π stacking interaction with an excited state intermolecular proton transfer probe 3-Hydroxynaphthoic acid revealed by experiments and molecular simulation","authors":"Priyanka Mukherjee ,&nbsp;Titas Kumar Mukhopadhyay ,&nbsp;Sagarika Sanyal ,&nbsp;Kaushik Kundu ,&nbsp;Rina Ghosh ,&nbsp;Sudeshna Shyam Chowdhury ,&nbsp;Sanjib Ghosh","doi":"10.1016/j.bpc.2025.107416","DOIUrl":"10.1016/j.bpc.2025.107416","url":null,"abstract":"<div><div>In biophysical studies involving proteins, the involvement of the intrinsic fluorophore Tryptophan and its energy transfer/binding interactions are already well-investigated areas. Theoretical studies have also been well corroborated with experimental findings. However, in polymeric Tryptophans (specifically homopolymers), several queries still need to be addressed – their structure, the environment of each Tryptophan and the binding preferences of the latter. This necessitated some detailed investigations on the poly-L-Tryptophan system both from experimental and theoretical standpoints. In this work, we have carried out both steady-state and time-resolved fluorescence studies along with low-temperature phosphorescence (LTP) of poly-L-tryptophan, and the nature of the emitting Tryptophan (Trp) residue in the latter has been characterized based on a comparison with the emission features of the parent monomer. The very large red-shift of the (0–0) band of phosphorescence in poly-L-Tryptophan has been explained through triplet-triplet energy transfer along with the structure of the latter which has been developed by theoretical modelling. The nature of the environment of the emitting Trp residue in poly-L-Trp has been compared with several multi-Tryptophan proteins where different Trp residues exhibit optically resolved (0–0) bands. The interaction of the excited state proton transfer (ESIPT) probe 3-hydroxynaphthoic acid (3-HNA) with poly-L-Trp has also been investigated in detail using fluorescence, LTP, and classical molecular dynamics simulations.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107416"},"PeriodicalIF":3.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper(II) enhances the antibacterial activity of nitroxoline against MRSA by promoting aerobic glycolysis","authors":"Xiaoyong Huang ,&nbsp;Huiting Yang ,&nbsp;Xiaomin Ren ,&nbsp;Qianqian Li ,&nbsp;Jianzhong Wang ,&nbsp;Jia Cheng ,&nbsp;Zilong Sun","doi":"10.1016/j.bpc.2025.107419","DOIUrl":"10.1016/j.bpc.2025.107419","url":null,"abstract":"<div><div>Nitroxoline (NIT) is an FDA-approved antibiotic with numerous pharmacological properties. However, the intricate connections between its metal-chelating ability and antimicrobial efficacy remain incompletely understood. The specific interactions of NIT with different metal ions were measured via UV–vis absorption spectroscopy. Here, we found that NIT can bind to various metal ions, including Cu²⁺, Fe²⁺, Zn²⁺ and Mn²⁺. However, the antimicrobial activity of NIT against methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) was significantly enhanced by the inclusion of Cu²⁺ as determined by a minimal inhibitory concentration (MIC) assay in Mueller-Hinton broth. The enhanced antibacterial effect was not influenced by the availability of oxygen. Mechanistically, Cu²⁺ promoted bacterial proliferation, increased the bacterial transmembrane electrical potential, and increased intracellular acidification. In addition, Cu²⁺ rewired bacterial metabolism, promoting the uptake of glucose with a lower level of ATP production. Pharmacological upregulation of glycolysis by VLX600 could potentiate the susceptibility of MRSA to NIT. Moreover, Cu²⁺ also significantly increased the survival rate of acutely infected larvae. These collective results underscore that the enhanced antibacterial efficacy of NIT by Cu²⁺ intricately involves aerobic glycolysis in MRSA.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107419"},"PeriodicalIF":3.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic molecular profiling of non-native N6-substitution effects on m6A binding to the YTH domains of human RNA m6A readers in diabetes","authors":"Yuting Li ,&nbsp;Peng Tan ,&nbsp;Qianpan Liu ,&nbsp;Huaixin Sun ,&nbsp;Yue Wang ,&nbsp;Siyi Chen ,&nbsp;Weixin Kong ,&nbsp;Xiaoyi Sun ,&nbsp;Xiang Shao","doi":"10.1016/j.bpc.2025.107417","DOIUrl":"10.1016/j.bpc.2025.107417","url":null,"abstract":"<div><div>The RNA <em>N</em>⁶-adenosine methylation, resulting in <em>N</em>⁶-methyl adenosine (m6A), is one of the most important post-transcriptional modification events in the eukaryotic transcriptome, which is dynamically regulated by methyltransferases (writers), recognition proteins (readers) and demethylases (erasers). Human has five m6A readers namely YTHDC1, YTHDC2, YTHDF1, YTHDF2 and YTHDF3 that specifically recognize and bind to the methylated m6A residue of RNA through their YT521-B homology (YTH) domains, which have been involved in the pathogenesis of diabetes mellitus and its diverse complications such as diabetic nephropathy. Instead of the native <em>N</em>⁶-methylation, we herein attempted to explore the molecular effect of various non-native <em>N</em>⁶-substitutions on adenosine (A) binding behavior to YTH domains. A systematic interaction profile of 40 reported <em>N</em>⁶-substituted adenosine (x6A) mononucleotides with 5 human reader YTH domains was created computationally. Heuristic clustering of the profile divided these YTH domains and these x6A mononucleotides into two subfamilies and three classes, respectively; they represent distinct intrinsic interaction modes between the domains and mononucleotides. Statistical survey unraveled that the volume (<em>V</em>_g) and hydrophobicity (<em>H</em>_g) of <em>N</em>⁶-substituted chemical groups exhibit linear and nonlinear correlations with the binding energy (Δ<em>G</em>_ttl) of x6A mononucleotides to YTH domains, respectively; <em>N</em>⁶-substitutions with moderate size and weak polarity are favorable for the x6A binding. From the profile the <em>N</em>⁶-bromomethyl adenosine (brm6A) was identified as a potent binder of YTHDF2 YTH domain; its affinity was improved significantly by 77.2-fold from A and considerably by 19.5-fold from m6A. Structural modeling observed that the <em>N</em>⁶-bromomethyl group of brm6A is tightly packed against an aromatic cage defined by the Trp432-Trp486-Trp491 triad of YTHDF2 YTH domain. Electron-correlation analysis revealed that the bromine atom can form geometrically and energetically satisfactory halogen-π interactions with the aromatic cage, thus conferring considerable affinity and specificity to the domain–brm6A interaction.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107417"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating thyroid hormone transport proteins disruption by nitrophenols through computational and spectroscopic analysis","authors":"Yanhong Zheng,&nbsp;Zeyu Song,&nbsp;Muwei Huang,&nbsp;Cancan Li,&nbsp;Chunke Nong,&nbsp;Tinghao Jiang,&nbsp;Zhanji Li,&nbsp;Zhongsheng Yi","doi":"10.1016/j.bpc.2025.107415","DOIUrl":"10.1016/j.bpc.2025.107415","url":null,"abstract":"<div><div>Thyroxine (T4), as a type of thyroid hormone (TH), is a key hormone in regulating human metabolism, growth and development, central nervous system functions, and energy balance. It relies on TH transport proteins to reach cells and exert its biological actions. However, the binding of nitrophenol pollutants to TH transport proteins prevents the delivery of thyroid hormones to cells, thereby inhibiting the effects of the hormones. This study combines spectroscopic experiments and computational simulations to explore the mechanism of nitrophenols' interference with TH transport proteins. Detailed information on the quenching mechanism, binding parameters, interaction forces, binding models, and conformational changes of nitrophenols (PNP), chlorinated nitrophenols (CNP), and brominated nitrophenols (BNP) with TH transport proteins is obtained through spectroscopic experiments. Nitrophenols are found to form hydrogen bonds with residues Lys15, Arg378, and Arg381, respectively, thereby displacing T4 at the binding site in the TH transport proteins. With an increasing number of halogen atoms, the affinity of halogenated nitrophenols for TH transport proteins intensifies. Computational simulations are used to further understand the binding modes and binding sites, providing molecular-level insights into the binding of NPs in the cavity of TH transport proteins. Theoretical evidence from molecular docking and molecular dynamics (MD) simulations supports the experimental findings.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107415"},"PeriodicalIF":3.3,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Substitutions at rheostat position 52 of LacI have long-range effects on the LacI conformational landscape","authors":"Nilusha L. Kariyawasam ,&nbsp;Anastasiia Sivchenko ,&nbsp;Liskin Swint-Kruse ,&nbsp;Paul E. Smith","doi":"10.1016/j.bpc.2025.107414","DOIUrl":"10.1016/j.bpc.2025.107414","url":null,"abstract":"<div><div>In proteins, amino acid changes at “rheostat” positions exhibit functional changes that vary with the substitution chosen: some substitutions enhance function, some are like wild-type, some are partially detrimental, while others abolish function. One way that substitutions might exert their complex effects is by altering protein conformational landscapes. To test this, we studied five substitutions of V52 in <em>E. coli</em> LacI, an experimentally-known rheostat position. For each variant, we mapped the accessible conformational landscapes by performing molecular dynamics simulations at ambient conditions and under three perturbations: increased pressure, binding to allosteric ligand “ONPF”, and ONPF plus pressure. The simulated DNA binding domain landscapes were compared to published experimentally-measured parameters, and the results suggest that complex combinations of dynamic parameters and/or additional simulations in the presence of DNA are needed to predict DNA binding specificity. For the variants regulatory domains all landscapes displayed boundaries similar to wild-type, but changes within the boundaries were unique. Of these, V52A/ONPF was striking: The regulatory domains for ONPF-bound, wild-type LacI are in an “Open” conformation and, experimentally, ONPF enhances DNA binding. Four variants responded to ONPF like wild-type, but ONPF binding to V52A shifted these domains to a “Closed” conformation that is associated with diminished DNA binding for wild-type LacI. This finding predicted that ONPF's allosteric regulation of V52A would change from “anti-inducer” to “inducer”, which we experimentally validated <em>in vivo</em> and <em>in vitro</em>. This supports the hypothesis that substituting rheostat positions can alter function by altering the relative populations on protein conformational landscapes.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107414"},"PeriodicalIF":3.3,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A semiempirical and machine learning approach for fragment-based structural analysis of non-hydroxamate HDAC3 inhibitors","authors":"Sk. Abdul Amin ,&nbsp;Lucia Sessa ,&nbsp;Rajdip Tarafdar ,&nbsp;Shovanlal Gayen ,&nbsp;Stefano Piotto","doi":"10.1016/j.bpc.2025.107409","DOIUrl":"10.1016/j.bpc.2025.107409","url":null,"abstract":"<div><div>Interest in HDAC3 inhibitors (HDAC3i) for pharmacological applications outside of cancer is growing. However, concerns regarding the possible mutagenicity of the commonly used hydroxamates (zinc-binding groups, ZBGs) are also increasing. Considering these concerns, non-hydroxamate ZBGs offer a promising alternative for the development of non-mutagenic HDAC3 inhibitors. Unfortunately, the quantum chemical space of non-hydroxamates has not been studied in detail. This study has three primary goals: (i) to perform semiempirical quantum chemical calculations, examining AM-1 model parameters relevant to zinc binding, (ii) to develop supervised mathematical learning models to train a diverse set of non-hydroxamate-based HDAC3i, and (iii) to apply fragment-based approaches to identify sub-structural fragments (fingerprints) that promote or hinder HDAC3 inhibitory activity through classification-based QSARs. In addition, flexible molecular docking analysis, 200 ns MD simulation, and free energy landscape (FEL) analysis further established the importance of identified fingerprints in the modulation of HDAC3 inhibitory activity. This comprehensive analysis of structural variations among non-hydroxamate HDAC3i provides valuable insights, contributing to the design of potential non-mutagenic HDAC3i.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107409"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unbiased clustering of residues undergoing synchronous motions in proteins using NMR spin relaxation data","authors":"V.S. Manu ,&nbsp;Giuseppe Melacini ,&nbsp;Evgenii L. Kovrigin ,&nbsp;J. Patrick Loria ,&nbsp;Gianluigi Veglia","doi":"10.1016/j.bpc.2025.107411","DOIUrl":"10.1016/j.bpc.2025.107411","url":null,"abstract":"<div><div>Biological macromolecules are dynamic entities that transition between various conformational states, often playing a vital role in biological functions. Their inherent flexibility spans a broad range of timescales. Motions occurring within the microsecond to millisecond range are especially important, as they are integral to processes such as enzyme catalysis, folding, ligand binding, and allostery. NMR Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion measurements are the preferred method for characterizing macromolecular motions at atomic resolution. However, it is still uncertain whether the functional motions of multiple residues in macromolecules need to be coordinated and/or synchronized within the protein matrix in order to perform the desired function. Here, we illustrate an unbiased method to analyze NMR relaxation dispersion and identify dynamic clusters of residues that fluctuate on similar timescales within proteins. The method requires relaxation dispersion data for backbone amides or side-chain methyl groups, which are globally fitted using the Bloch-McConnell equations for each pair of residues. The goodness of the pairwise fitting serves as a metric to construct two-dimensional synchronous dynamics (SyncDyn) maps, allowing us to identify residue clusters whose dynamics are influenced by ligand binding. We applied our method to the catalytic subunit of the cAMP-dependent protein kinase A (PKA<img>C) and the T17A mutant of ribonuclease A (RNAse A). The SyncDyn maps for PKA-C showed distinct clusters of residues located in critical allosteric sites. Nucleotide binding activates the movement of residues at the interface between the two lobes and also those distal to the active site. In the case of RNAse A, the SyncDyn maps show that residues fluctuating with the same time scale are interspersed in both lobes of the enzyme. Overall, our approach eliminates arbitrary manual selection of residues for dynamic clustering and objectively identifies all possible residue pairs that fluctuate synchronously, <em>i.e.</em> on the same timescale.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107411"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting human prostaglandin reductase 1 with Licochalcone A: Insights from molecular dynamics and covalent docking studies","authors":"Sara Abigail Ramírez-Cortés ,&nbsp;Adrián Durán-Vargas ,&nbsp;Jesús Antonio Rauda-Ceja ,&nbsp;Paola Mendoza-Espinosa ,&nbsp;Luis Fernando Cofas-Vargas ,&nbsp;Armando Cruz-Rangel ,&nbsp;Julio Isael Pérez-Carreón ,&nbsp;Enrique García-Hernández","doi":"10.1016/j.bpc.2025.107410","DOIUrl":"10.1016/j.bpc.2025.107410","url":null,"abstract":"<div><div>Prostaglandin reductase 1 (PTGR1) is an NADPH-dependent enzyme critical to eicosanoid metabolism. Its elevated expression in malignant tumors often correlates with poor prognosis due to its role in protecting cells against reactive oxygen species. This study explores the inhibitory potential of licochalcone A, a flavonoid derived from Xinjiang licorice root, on human PTGR1. Using molecular dynamics simulations, we mapped the enzyme's conformational landscape, revealing a low-energy, rigid-body-like movement of the catalytic domain relative to the nucleotide-binding domain that governs PTGR1's transition between open and closed states. Simulations of NADPH-depleted dimer and NADPH-bound monomer highlighted the critical role of intersubunit interactions and coenzyme binding in defining PTGR1's conformational landscape, offering a deeper understanding of its functional adaptability as a holo-homodimer. Covalent docking, informed by prior chemoproteomic cross-linking data, revealed a highly favorable binding pose for licochalcone A at the NADPH-binding site. This pose aligned with a transient noncovalent binding pose inferred from solvent site-guided molecular docking, emphasizing the stereochemical complementarity of the coenzyme-binding site to licochalcone A. Sequence analysis across PTGR1 orthologs in vertebrates and exploration of 3D structures of human NADPH-binding proteins further underscore the potential of the coenzyme-binding site as a scaffold for developing PTGR1-specific inhibitors, positioning licochalcone A as a promising lead compound.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107410"},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of ergosterol or cholesterol on the morphology and dynamics of the POPC/sphingomyelin bilayer","authors":"Fernando Favela-Rosales ,&nbsp;Jorge Hernández-Cobos ,&nbsp;Arturo Galván-Hernández ,&nbsp;Omar Hernández-Villanueva ,&nbsp;Iván Ortega-Blake","doi":"10.1016/j.bpc.2025.107408","DOIUrl":"10.1016/j.bpc.2025.107408","url":null,"abstract":"<div><div>Phase segregation and domain formation in cell membranes and model lipid bilayers have become a relevant topic in the last decades due to their role in important cell functions such as signaling and molecule-membrane interactions. To date, the most accepted explanation for the formation of these domains in mammalian cells is that cholesterol-enriched sphingomyelin patches of membrane form because of the preferential interaction between them. However, detailed information on molecular interactions within cholesterol-containing bilayers and their comparison with other sterol-containing bilayers, such as those containing ergosterol, is needed to understand the role these molecules have. Recent experimental findings have shown sterol-dependent differences in the morphology of supported lipid bilayers, but the molecular basis for these differences remains unclear. This work provides a molecular explanation for these differences using atomistic Molecular Dynamics simulations of lipid bilayers composed of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and N-palmitoyl-D-erythro-sphingosylphosphorylcholine (PSM) with 20 mol% of cholesterol or ergosterol. Atomic force microscopy was used to validate the simulation. The simulation ran for 11 μs and revealed that both sterols affect the morphology of the membrane. Key findings include: ergosterol induces greater order in PSM domains compared to cholesterol, lipid diffusion constants are lower in ergosterol-containing membranes, sterol flip-flop rates are significantly reduced in ergosterol-containing membranes and ergosterol leads to greater PSM-sterol enrichment. These molecular-level differences provide insight into the experimentally observed variations in domain formation and membrane properties between cholesterol and ergosterol-containing bilayers. Our findings contribute to the understanding of sterol-specific effects on membrane organization and dynamics, with potential implications for cellular processes and drug interactions in different organisms.</div></div><div><h3>Statement of significance</h3><div>This study advances our understanding of how different sterols influence membrane properties through molecular dynamics simulations of three-component lipid membranes. Specifically, we investigate the effects of two major sterols: ergosterol, predominantly found in plants and fungi, and cholesterol, characteristic of mammalian cells. While extensive research has elucidated cholesterol's impact on lipid bilayers, studies on ergosterol's effects are comparatively limited. Our work provides a comprehensive comparison of these sterols, highlighting their similarities and differences. These insights not only enhance our knowledge of cell membrane structure and function, but also contribute to our understanding of selective drug permeability across membranes. This research has potential implications for both fundamental cell biology and pharmaceutical applications.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107408"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}