European Biophysics Journal最新文献_第5页

Magnetic field based investigation of Brugada syndrome 基于磁场的Brugada综合征研究。

IF 2.4 4区生物学

European Biophysics Journal Pub Date : 2026-03-04 DOI: 10.1007/s00249-026-01826-7

Martina Nicoletti, Anna Crispino, Alessandro Loppini, Alessio Gizzi, Letizia Chiodo, Christian Cherubini, Simonetta Filippi

{"title":"Magnetic field based investigation of Brugada syndrome","authors":"Martina Nicoletti, Anna Crispino, Alessandro Loppini, Alessio Gizzi, Letizia Chiodo, Christian Cherubini, Simonetta Filippi","doi":"10.1007/s00249-026-01826-7","DOIUrl":"10.1007/s00249-026-01826-7","url":null,"abstract":"<div>\u0000 \u0000 <p>Brugada syndrome (BrS) is an inherited cardiac disorder associated with and increased risk of sudden cardiac death. The syndrome is associated with a complex current distribution and repolarization dispersion. The traditional methods for the diagnosis rely on standard electrocardiographic (ECG) assessment of the cardiac dynamics. Recent advancements in magnetocardiography suggest that the magnetic-field based investigation of cardiac electrophysiology could offer novel perspectives for the investigation of current abnormalities in BrS patients which go beyond the conventional ECG capabilities to capture intricate current distributions. In this work, we propose a framework for the magnetic analysis of action potential disturbances in Brugada syndrome. We exploit a 1D reduced-order cable geometry for analyzing the relation between the pathological electrical activity in saddleback and coved type BrS and the corresponding magnetic field. Also, we compute transmural pseudo-magnetocardiograms and demonstrate their capabilities of detecting both types of BrS. Overall, our result highlight the potential of magnetic-field oriented investigation of cardiac disturbances related to BrS.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 :","pages":"187 - 197"},"PeriodicalIF":2.4,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00249-026-01826-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353228","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}

引用次数: 0

Weak protein–bicelle binding quantification via surface-based DNA nanolevers 基于表面DNA纳米试剂的弱蛋白-单细胞结合定量研究。

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-03-02 DOI: 10.1007/s00249-026-01829-4

Sophie Combet, Raphael Dos Santos Morais, Audrey Comte, Angélique Cheron, Emeline Barbet-Massin, Hanna Müller-Landau, Olivier Delalande, Jean-François Hubert, Jean-Baptiste Charbonnier, Paloma Fernández Varela

{"title":"Weak protein–bicelle binding quantification via surface-based DNA nanolevers","authors":"Sophie Combet, Raphael Dos Santos Morais, Audrey Comte, Angélique Cheron, Emeline Barbet-Massin, Hanna Müller-Landau, Olivier Delalande, Jean-François Hubert, Jean-Baptiste Charbonnier, Paloma Fernández Varela","doi":"10.1007/s00249-026-01829-4","DOIUrl":"10.1007/s00249-026-01829-4","url":null,"abstract":"<div>\u0000 \u0000 <p>To investigate how human dystrophin associates with biomimetic phospholipid bicelles, we applied switchSENSE<sup>®</sup>, a fluorescence-based biosensing technology that employs dynamic DNA nanolevers in a microfluidic environment with minimal material requirements. We show that switchSENSE<sup>®</sup> enables real-time kinetic analysis of weak and transient interactions, offering a clear advantage over classical biophysical methods that often fail to capture low-affinity protein-lipid binding. Focusing on two functionally relevant central-domain dystrophin fragments (R1-3 and R11-15), we quantified binding to zwitterionic and anionic bicelles using two complementary assay orientations: proteins immobilized with bicelles as analytes, and the reverse. Both yielded consistent micromolar affinities, in line with prior microscale thermophoresis results, but uniquely provided kinetic rate constants. This represents the first kinetic characterization of dystrophin-bicelle interactions, revealing that weak affinity is largely driven by rapid dissociation. Notably, R11-15 exhibited faster association and slower dissociation than R1-3, indicating a more stable and sustained lipid interaction. Beyond advancing mechanistic insight into dystrophin’s reversible membrane association – a process thought to stabilize sarcolemmal integrity during muscle contraction and elongation -, our study highlights switchSENSE<sup>®</sup> as a versatile platform for quantifying weak protein-lipid interactions. By enabling kinetic resolution of interactions at the edge of conventional detection limits, switchSENSE<sup>®</sup> provides a powerful tool for dissecting the dynamic interplay between structural proteins and lipid assemblies.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 :","pages":"379 - 390"},"PeriodicalIF":2.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00249-026-01829-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324150","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}

引用次数: 0

Effects of synergistic/antagonistic interactions between spermidine (3+) and putrescine (2+) on gene expression through higher-order DNA structural modification 亚精胺（3+）和腐胺（2+）协同/拮抗作用通过高阶DNA结构修饰对基因表达的影响

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-03-02 DOI: 10.1007/s00249-026-01831-w

Haruto Ogawa, Takashi Nishio, Yuko Yoshikawa, Takahiro Kenmotsu, Kenichi Yoshikawa

{"title":"Effects of synergistic/antagonistic interactions between spermidine (3+) and putrescine (2+) on gene expression through higher-order DNA structural modification","authors":"Haruto Ogawa, Takashi Nishio, Yuko Yoshikawa, Takahiro Kenmotsu, Kenichi Yoshikawa","doi":"10.1007/s00249-026-01831-w","DOIUrl":"10.1007/s00249-026-01831-w","url":null,"abstract":"<div>\u0000 \u0000 <p>Polyamines are essential cationic biomolecules that interact with negatively charged biomolecules, such as DNA, RNA, and proteins, thereby modulating their structure and function. Although spermidine(3+) and spermine(4+) often act synergistically, studies have indicated that putrescine(2+) can act antagonistically toward spermidine and other polyamines. To elucidate the associated synergistic/competitive effects, we investigated how putrescine and spermidine, when present together, cause higher-order structural changes in DNA and gene expression. Cell-free luciferase assays revealed that putrescine and spermidine exerted either synergistic or antagonistic effects on gene expression depending on their concentration. Millimolar concentrations of putrescine increased gene expression when combined with spermidine, but higher concentrations (e.g., 10 mM) inhibited expression. Atomic force microscopy revealed that structural changes in DNA were linked to changes in gene expression activity. These characteristic effects on DNA conformation and gene expression caused by the coexistence of putrescine and spermidine are examined in terms of physicochemical correlations among charged species, including the higher-order structure of negatively charged DNA, polycationic polyamines, and small counterions. At relatively low concentrations of polyamines, the effective negative charge of DNA decreases because of the cooperative effect between putrescine and spermidine. In contrast, at higher concentrations, the antagonistic effect becomes apparent as competitive interaction arises through counterion translational entropy. Notably, such bimodal effects could constitute a relatively general mechanism in the solution environment of living matter.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 4","pages":"607 - 619"},"PeriodicalIF":2.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00249-026-01831-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324079","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}

引用次数: 0

Clinical use of electrodermal activity and current developments 皮电活动的临床应用及最新进展。

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-02-25 DOI: 10.1007/s00249-026-01820-z

Ali Yucel Kara, Nazan Dolu, Ferhan Esen

{"title":"Clinical use of electrodermal activity and current developments","authors":"Ali Yucel Kara, Nazan Dolu, Ferhan Esen","doi":"10.1007/s00249-026-01820-z","DOIUrl":"10.1007/s00249-026-01820-z","url":null,"abstract":"<div>\u0000 \u0000 <p>Electrodermal activity (EDA) represents a valuable non-invasive measure of sympathetic nervous system function with expanding applications in both research and clinical settings. The physiological foundations of EDA lie in eccrine sweat gland activity. This activity is controlled by sympathetic cholinergic innervation through complex central neural pathways. Clinical applications span multiple domains, including psychiatry, neurology, and cognitive assessment, where distinct EDA patterns characterize conditions such as anxiety disorders, depression, schizophrenia, peripheral neuropathies, and neurodegenerative diseases. Significant technological advancements have revolutionized EDA measurement, transitioning from controlled laboratory environments to wearable continuous monitoring systems suitable for naturalistic assessment. Advanced sensor technologies, signal processing algorithms, and artificial intelligence methods have been integrated. This integration has substantially improved data acquisition and interpretation capabilities. The development of multiparametric approaches that combine EDA with complementary physiological measures offers a more comprehensive assessment of autonomic function. Challenges remain in measurement standardization and interpretation of individual variability. Despite these challenges, EDA demonstrates substantial potential for enhancing diagnostic precision, facilitating personalized interventions, and advancing our understanding of autonomic function across health and disease states.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 4","pages":"533 - 549"},"PeriodicalIF":2.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281760","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}

引用次数: 0

Perspective on 3D microfluidic eye-on-a-chip technology for ophthalmological research 三维微流控眼芯片技术在眼科研究中的应用前景。

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-02-20 DOI: 10.1007/s00249-026-01824-9

Gözde Narin, Onur İnam, Mehmet Yuksekkaya

{"title":"Perspective on 3D microfluidic eye-on-a-chip technology for ophthalmological research","authors":"Gözde Narin, Onur İnam, Mehmet Yuksekkaya","doi":"10.1007/s00249-026-01824-9","DOIUrl":"10.1007/s00249-026-01824-9","url":null,"abstract":"<div>\u0000 \u0000 <p>The quality of life of millions of people worldwide is reduced due to eye defects. A predictable perspective is needed to express ophthalmology and drug development studies using functional and simpler models and systems to explain complex mechanisms, such as the eye. Organ-on-a-chip (OoC) technology is used to develop models under in vitro conditions, according to the needs of specific tissue or organ studies. Cellular functions of cells in a three-dimensional (3D) cell culture environment are expected to be more efficient than those of monolayer cells in a two-dimensional (2D) culture. This situation is similar to that of planned studies on eye tissues. Efficient results in terms of cell-cell interactions were obtained in eye-on-chip studies, where 3D cell culture was created with a perfusion system in microfluidic chip channels created using materials such as polymethylmethacrylate (PMMA) and polydimethylsiloxane (PDMS). Recently, eye-chip technology has been used to mimic eye tissues and reduced the economic burden of pharmacological studies. Eye-chip studies designed for cornea, choroid, retina, tear film, and eye disease models using retinal organoids, cell lines, and stem cells yielded fruitful results in the literature. Lower-cost and environmentally friendly ocular tissue models are required for toxicity tests of pharmacological drugs used as a treatment method. In this review, studies on the microfluidics-organized eye-chip technology are reviewed. It is important to conduct studies on the mechanisms of eye disease and eye drop development. Therefore, studies on this new technology developed by the combined use of eye diseases, biophysics, and microfluidics are discussed.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 4","pages":"523 - 531"},"PeriodicalIF":2.3,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256902","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}

引用次数: 0

Structure-based identification, phosphorylation, cyclization and engineering of a self-binding peptide carboxy-terminal to EGFR kinase domain by integrating dynamics simulation, energetics calculation and fluorescence analysis 结合动力学模拟、能量学计算和荧光分析，基于结构的EGFR激酶结构域自结合肽羧基端的鉴定、磷酸化、环化和工程。

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-02-20 DOI: 10.1007/s00249-026-01823-w

Jingjing Chen, Tianyu Wang, Lijuan Shi

{"title":"Structure-based identification, phosphorylation, cyclization and engineering of a self-binding peptide carboxy-terminal to EGFR kinase domain by integrating dynamics simulation, energetics calculation and fluorescence analysis","authors":"Jingjing Chen, Tianyu Wang, Lijuan Shi","doi":"10.1007/s00249-026-01823-w","DOIUrl":"10.1007/s00249-026-01823-w","url":null,"abstract":"<div>\u0000 \u0000 <p>Epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of many human cancers. In addition to the extracellular ligand-binding domain and intracellular kinase domain of EGFR that have been widely investigated over the past decades, the function and role of the carboxy-terminal tail (C-tail) still remains largely unexplored to date. In this study, the intramolecular interaction of EGFR kinase domain with C-tail was characterized systematically at structural, energetic and dynamic levels; a 13-mer hotspot segment (<sup>1007</sup>MDDVVDADEYLIP<sup>1019</sup>) was identified as self-binding peptide (SBP) in the first ~ 80-residue region of C-tail that plays an important role in the interaction, in which the Tyr1016 residue serves as a trigger to regulate the binding state of SBP, that is, the SBP can bind to/unbind from the kinase domain upon pTyr1016 dephosphorylation/Tyr1016 phosphorylation, thus working as a molecular switch to control the auto-inhibitory state of the C-tail. The SBP-derived peptide is intrinsically disordered and thus only exhibits a moderate affinity to EGFR kinase domain, which can be constrained into an ordered one-turn helical conformation by designing a disulfide cyclization across its residue foothold[1012,1015]. The designed cyclic peptide is an effective self-competitor with the native SBP segment for their cognate docking site, which can competitively disrupt the native intramolecular interaction between EGFR kinase domain and C-tail with a high potency. It is suggested that the SBP molecular switch is responsible for the dynamic regulation of domain–tail interactions triggered by Tyr1016 phosphorylation state, which may further influence the EGFR dimerization, activation and signaling.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 4","pages":"595 - 605"},"PeriodicalIF":2.3,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256825","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}

引用次数: 0

Nitroxide spin, non-canonical amino acids and SDSL-EPR spectroscopy: a winning combination for protein dynamics studies 氮氧化物自旋，非规范氨基酸和SDSL-EPR光谱：蛋白质动力学研究的成功组合。

IF 2.3 4区生物学

European Biophysics Journal Pub Date : 2026-02-11 DOI: 10.1007/s00249-025-01806-3

Maxime Bizet, Áron Balázsi, Colette Maignet-Magard, Pierre Dorlet, Emilien Etienne, Guillaume Gerbaud, Gilles Truan, Deborah Byrne, Tamás Kálai, Marlène Martinho

{"title":"Nitroxide spin, non-canonical amino acids and SDSL-EPR spectroscopy: a winning combination for protein dynamics studies","authors":"Maxime Bizet, Áron Balázsi, Colette Maignet-Magard, Pierre Dorlet, Emilien Etienne, Guillaume Gerbaud, Gilles Truan, Deborah Byrne, Tamás Kálai, Marlène Martinho","doi":"10.1007/s00249-025-01806-3","DOIUrl":"10.1007/s00249-025-01806-3","url":null,"abstract":"<div>\u0000 \u0000 <p>Site-Directed Spin Labelling combined with Electron Paramagnetic Resonance (SDSL-EPR) is a powerful technique for studying protein dynamics at the molecular level. This method involves introducing a paramagnetic label, typically at a cysteine residue at a selected site. Continuous wave (cw) EPR allows studying protein dynamics in the nano-second time scale, while using Double Electron Electron Resonance (DEER), nanometre-scale (2–6 nm) distance measurements can be obtained by detecting dipolar interaction between two paramagnetic labels. Here, we describe the application of the SDSL-EPR approach to the soluble form of the <i>Homo sapiens</i> flavoprotein cytochrome P450 reductase, utilizing its stabilized semi-quinone state (FMNH<sup>•</sup>) as an intrinsic paramagnetic centre. Additionally, the non-canonical amino acid (ncaa) <i>p</i>AzPhe (para-azidophenylalanine) was site-specifically incorporated into the FAD (Flavin Adenine Dinucleotide) and FMN (Flavin MonoNucleotide) domains, and labelled with the recently developed nitroxide probes <sup>14/15</sup>N-HO-5223. DEER measurements were performed between the FMNH<sup>•</sup> centre and the nitroxide label, providing structural insights into the protein. This protocol details the synthesis of the <sup>14/15</sup>N-HO-5223 label, the incorporation of <i>p</i>AzPhe at the two specific positions, site-specific labelling and EPR measurements, offering a comprehensive workflow/protocol for applying SDSL-EPR to flavoproteins and beyond.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 :","pages":"347 - 365"},"PeriodicalIF":2.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155492","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}

引用次数: 0

The European Biophysics Journal Prizes 2025: Recognising biophysical science at sub-cellular, cellular and tissue levels of organisation 2025年欧洲生物物理杂志奖：承认亚细胞、细胞和组织水平的生物物理科学。

IF 2.4 4区生物学

European Biophysics Journal Pub Date : 2026-02-06 DOI: 10.1007/s00249-026-01822-x

Robert J. C. Gilbert

引用次数: 0

The role of heterogeneity of intersubunit interfaces in the outer membrane leaflet in maintaining GABAA receptor activity 外膜小叶亚基界面异质性在维持GABAA受体活性中的作用。

IF 2.4 4区生物学

European Biophysics Journal Pub Date : 2026-02-04 DOI: 10.1007/s00249-026-01816-9

Alexey Rossokhin

{"title":"The role of heterogeneity of intersubunit interfaces in the outer membrane leaflet in maintaining GABAA receptor activity","authors":"Alexey Rossokhin","doi":"10.1007/s00249-026-01816-9","DOIUrl":"10.1007/s00249-026-01816-9","url":null,"abstract":"<div><p>GABA type A receptors (GABA<sub>A</sub>R) mediate fast inhibition processes in the CNS. We proposed that β2 Arg269 (19′) residue maintains the activated state of GABA<sub>A</sub>R by wedging its bulky side chain into β(+)/α(–) transmembrane interfaces in the outer membrane leaflet. To explore this hypothesis, we used the cryo-EM structure (6X3Z) of agonist-bound α1β2γ2 GABA<sub>A</sub>R and molecular dynamics. We found that the Arg19′ side chain tends to adopt a horizontal conformation at β(+)/α(–) interfaces, in which it forms strong contacts with both interface sides, thereby wedging the interfaces. We found that due to the presence of the γ subunit, two β(+)/α(−) interfaces are not identical in terms of the Arg19′ side chain dynamics. At other interfaces, the Arg19′ side chain adopts a vertical conformation in which it forms strong contacts only with residues from the principal subunit. We identified residues 15′, 20′, and 29′ of the principal subunits responsible for this difference in the Arg19′ side chain dynamics. We constructed models of mutant GABA<sub>A</sub>R in which the Arg19′ side chain dynamics in the two above interface groups are opposite to those of wild-type receptor. In this work, we proposed a new molecular mechanism for maintaining GABA<sub>A</sub>R in the activation state.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 1","pages":"63 - 77"},"PeriodicalIF":2.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117410","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}

引用次数: 0

Exploring the GDP binding to KRas WT, G12C, G12D, G12R, and G12V and bound with MRTX1133 using steered molecular dynamics 利用定向分子动力学方法探索GDP与KRas WT、G12C、G12D、G12R、G12V的结合以及与MRTX1133的结合。

IF 2.4 4区生物学

European Biophysics Journal Pub Date : 2026-02-04 DOI: 10.1007/s00249-026-01817-8

Abdulaziz Alamri, Showkat Ahmad Mir, Shahnawaz Khan, Irshad Ahmad, Jamoliddin Razzokov, Binata Nayak

{"title":"Exploring the GDP binding to KRas WT, G12C, G12D, G12R, and G12V and bound with MRTX1133 using steered molecular dynamics","authors":"Abdulaziz Alamri, Showkat Ahmad Mir, Shahnawaz Khan, Irshad Ahmad, Jamoliddin Razzokov, Binata Nayak","doi":"10.1007/s00249-026-01817-8","DOIUrl":"10.1007/s00249-026-01817-8","url":null,"abstract":"<div>\u0000 \u0000 <p>The oncogenic KRas protein is a crucial therapeutic target for cancer, but the efficacy of inhibitors against its variants remains complex. Using steered molecular simulations we quantified the binding free energies (ΔG<sub>bind</sub>) of GDP to wild-type (WT) KRas and its key oncogenic mutants <sup>G12C, G12D, G12R, and G12V,</sup> with and without MRTX1133 a potential inhibitor of the KRas G12D variant. In this study we highlighted the cooperative effect of GDP on holo KRas and KRas-bound MRTX1133, including variants. In comparison to the WT’s baseline of KRas, the ΔG<sub>bind</sub> of GDP was found to be -49 ± 3.3 kJ/mol. The ΔG<sub>bind</sub> increases significantly against variants G12C, G12D, G12R, and G12V, ranging from − 99.2 ± 12.3 to -154.8 ± 5.05 kJ/mol), respectively, resulting in higher effectiveness two to three times more against halo KRas variants. Furthermore, the ΔGbind of GDP against WT, KRas complexed with MRTX1133, was found to be -100.5 kJ/mol, whereas the ΔGbind against variants G12C, G12D, G12R, and G12V ranges from 110.6 ± 14.4 to -113.2 ± 2.7 kJ/mol, respectively. The binding affinities confirmed that GDP is a fundamental driver of oncogenicity. This reveals a significant cooperative effect where the presence of MRTX1133 paradoxically strengthened subsequent GDP binding in all systems. These findings provide a molecular-level explanation for the aggressiveness of KRas mutants. More importantly, this study reveals a potentially counterproductive mechanism for the G12R and G12V variants, where the inhibitor may inadvertently hyper-stabilize the active oncogenic state. This study highlights the critical need for mutation-specific strategies in designing Pan-KRas inhibitors.</p>\u0000 </div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 1","pages":"79 - 88"},"PeriodicalIF":2.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117387","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}

引用次数: 0