Biophysical chemistry最新文献

{"title":"Molecular dynamics study on clustered DNA damage: AP sites on the same strand","authors":"Kazushi Terakawa ,&nbsp;Susumu Fujiwara ,&nbsp;Tomoko Mizuguchi ,&nbsp;Hiroaki Nakamura ,&nbsp;Ken Akamatsu ,&nbsp;Naoya Shikazono ,&nbsp;Yoshiteru Yonetani","doi":"10.1016/j.bpc.2025.107394","DOIUrl":"10.1016/j.bpc.2025.107394","url":null,"abstract":"<div><div>Although radiation-induced clustered DNA damage can have critical biological consequences, the underlying molecular mechanisms remain unclear. To explore the effect of clustered DNA damage on DNA structure and dynamics, we performed molecular dynamics simulations on damaged DNA with two AP sites on the same strand, that is, a tandem AP cluster. The results showed that the cluster insertion of the two AP sites had a significant impact on the DNA's local and global structures. Local structural deformations as well as the extrahelical form, AP-base pairs, and irregular base pairs were frequently observed. Unlike a single AP site, the tandem AP cluster revealed that these local structural features occurred simultaneously within a small separation. Moreover, we found that the presence of tandem AP sites induced global bending of DNA. This suggests that the present case with tandem AP sites may have a non-negligible impact on the biological function of damage repair.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"319 ","pages":"Article 107394"},"PeriodicalIF":3.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073666","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":"SPR is a fast and straightforward method to estimate the binding constants of cyclic dinucleotides to their binding partners, such as STING or poxin","authors":"Hagen Sülzen,&nbsp;Martin Klima,&nbsp;Vojtech Duchoslav,&nbsp;Evzen Boura","doi":"10.1016/j.bpc.2025.107392","DOIUrl":"10.1016/j.bpc.2025.107392","url":null,"abstract":"<div><div>The development of small molecule drugs that target protein binders is the central goal in medicinal chemistry. During the lead compound development process, hundreds or even thousands of compounds are synthesized, with the primary focus on their binding affinity to protein targets. Typically, IC₅₀ or EC₅₀ values are used to rank these compounds. While thermodynamic values, such as the dissociation constant (KD), would be more informative, they are experimentally less accessible. In this study, we compare isothermal calorimetry (ITC) with surface plasmon resonance (SPR) using human STING, a key protein of innate immunity, and several cyclic dinucleotides (CDNs) that serve as its ligands. We demonstrate that SPR, with recent technological advancements, provides KDs that are sufficiently accurate for drug development purposes. To illustrate the versatility of our approach, we also used SPR to estimate the KD of poxin binding to cyclic GMP-AMP (cGAMP) that serves as a second messenger in the innate immune system. In conclusion, SPR offers a high benefit-to-cost ratio, making it an effective tool in the drug design process.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"319 ","pages":"Article 107392"},"PeriodicalIF":3.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027809","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":"Mapping conformational landscape in protein folding: Benchmarking dimensionality reduction and clustering techniques on the Trp-Cage mini-protein","authors":"Sayari Bhattacharya,&nbsp;Suman Chakrabarty","doi":"10.1016/j.bpc.2025.107389","DOIUrl":"10.1016/j.bpc.2025.107389","url":null,"abstract":"<div><div>Quantitative characterization of protein conformational landscapes is a computationally challenging task due to their high dimensionality and inherent complexity. In this study, we systematically benchmark several widely used dimensionality reduction and clustering methods to analyze the conformational states of the Trp-Cage mini-protein, a model system with well-documented folding dynamics. Dimensionality reduction techniques, including Principal Component Analysis (PCA), Time-lagged Independent Component Analysis (TICA), and Variational Autoencoders (VAE), were employed to project the high-dimensional free energy landscape onto 2D spaces for visualization. Additionally, clustering methods such as K-means, hierarchical clustering, HDBSCAN, and Gaussian Mixture Models (GMM) were used to identify discrete conformational states directly in the high-dimensional space. Our findings reveal that density-based clustering approaches, particularly HDBSCAN, provide physically meaningful representations of free energy minima. While highlighting the strengths and limitations of each method, our study underscores that no single technique is universally optimal for capturing the complex folding pathways, emphasizing the necessity for careful selection and interpretation of computational methods in biomolecular simulations. These insights will contribute to refining the available tools for analyzing protein conformational landscapes, enabling a deeper understanding of folding mechanisms and intermediate states.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"319 ","pages":"Article 107389"},"PeriodicalIF":3.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036684","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":"The role of nonlinear axonal membrane capacitance in modulating ion channel cooperativity in action potential dynamics: Studies on Hodgkin-Huxley's model","authors":"Jitender Kumar ,&nbsp;Patrick Das Gupta ,&nbsp;Subhendu Ghosh","doi":"10.1016/j.bpc.2025.107391","DOIUrl":"10.1016/j.bpc.2025.107391","url":null,"abstract":"<div><div>Hodgkin-Huxley's (HH) model of action potential (AP) has been modified in view of the nonlinear membrane capacitance of the axon of a neuron as well as the cooperation among the participating ion channels in the axon. Previous studies of action potential behavior based on computational analysis of modified HH models with either nonlinear axonal membrane capacitance or ion channel cooperativity show significant changes in action potential dynamics, e.g. AP peak, hyperpolarization amplitude, spike threshold, rapid onset, etc. As shown in the present paper, the combined effect of the nonlinear capacitance and ion channel cooperativity displays qualitatively similar results that are quantitatively different. For example, the nonlinear membrane capacitance leads to a reduction in the ion channel cooperativity effect on the action potential dynamics. The reason for this combined effect is thought to be axonal membrane distortion and depolarization caused by the varying membrane potential.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"319 ","pages":"Article 107391"},"PeriodicalIF":3.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073668","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":"Nano-viscosimetry analysis of membrane disrupting peptide magainin2 interactions with model membranes","authors":"Sara Pandidan,&nbsp;Adam Mechler","doi":"10.1016/j.bpc.2025.107390","DOIUrl":"10.1016/j.bpc.2025.107390","url":null,"abstract":"<div><div>The rapid spread of antibiotic-resistant strains of bacteria has created an urgent need for new alternative antibiotic agents. Membrane disrupting antimicrobial peptides (AMPs): short amino acid sequences with bactericidal and fungicidal activity that kill pathogens by permeabilizing their plasma membrane may offer a solution for this global health crisis. Magainin 2 is an AMP secreted by the African clawed frog (<em>Xenopus laevis</em>) that is described as a toroidal pore former membrane disrupting AMP. Magainin 2 is one of the most thoroughly studied AMPs, yet its mechanism of action is still largely hypothetical: visual evidence of the pore formation is lacking, and the molecular mechanism leading to pore formation is still debated. In the present study, quartz crystal microbalance (QCM) based viscoelastic fingerprinting analysis supported by dye leakage experiments and atomic force microscopy (AFM) imaging was used to glean deeper insights into the mechanism of action. The effect of membrane charge, acyl chain unsaturation and cholesterol concentration were also investigated. The results show lipid specific disruptive mechanism of magainin 2. QCM nano-viscometry measurements revealed the presence of distinct stages in the mechanism of magainin 2 action that, with dye leakage data, confirm the existence of an initial transient pore stage that may result in peptide flip-flop between the outer and inner membrane leaflets. There is evidence of a further mechanistic stage at high peptide concentrations that is consistent with membrane collapse into a peptide-lipid mixed phase that is distinct from the transient pore formation. The results confirm some of the earliest hypotheses about magainin 2 action, while also highlighting the membrane modulating effect of this peptide.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107390"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969550","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":"Molecular dynamics of SARS-CoV-2 omicron variants from Philippine isolates against hesperidin as spike protein inhibitor","authors":"June Alexis A. Santos ,&nbsp;Searle S. Duay","doi":"10.1016/j.bpc.2024.107387","DOIUrl":"10.1016/j.bpc.2024.107387","url":null,"abstract":"<div><div>SARS-CoV-2 remains a global threat with new sublineages posing challenges, particularly in the Philippines. Hesperidin (HD) is being studied as a potential prophylactic for COVID-19. However, the virus's rapid evolution could alter how HD binds to it, affecting its effectiveness. Here, we study the mutation-induced variabilities of HD dynamics and their effects on molecular energetics in SARS-CoV-2 spike receptor complex systems. We considered eight different point mutations present in the Omicron variant. Root-mean-square deviation and binding energy analysis showed that S477N and Omicron did not eject HD throughout the simulation. Hydrogen bond distribution analysis highlighted the involvement of hydrogen bonding in mutant-HD stabilization, especially for S477N and Omicron. Root-mean-square fluctuation analysis revealed evidence of Y505H destabilization on complex systems, while distal-end loop mutations increased loop flexibility for all models bearing the three mutations. Per-residue energy decomposition demonstrated that Q493R substitution increased HD interaction. Free energy landscape and essential dynamics through principal component analysis provided insights into the conformational subspace distribution of mutant model molecular dynamics trajectories. In conclusion, significant mutations contributed to the HD interaction in different ways. S477N has shown significant binding contributions through favorable ligand interaction, while other mutations contribute via conformational modifications, increased affinity due to sidechain mutations, and increased loop flexibility.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107387"},"PeriodicalIF":3.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913828","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":"Macromolecular interaction mechanism of the bacteriocin EntDD14 with the receptor binding domain (RBD) for the inhibition of SARS-CoV-2 and the JN.1 variant: Biomedical study based on elastic networks, stochastic Markov models, and macromolecular volumetric analysis","authors":"Luis Moncayo Molina ,&nbsp;María Erlinda Aguaiza Pichazaca ,&nbsp;José Isidro Yamasqui Padilla ,&nbsp;María Eufemia Pinos Calle ,&nbsp;Karla Maribel Yamasqui Pinos ,&nbsp;Arlene Cardozo Urdaneta ,&nbsp;Carla Lossada ,&nbsp;Yovani Marrero-Ponce ,&nbsp;Felix Martinez-Rios ,&nbsp;Ysaías J. Alvarado ,&nbsp;Aleivi Pérez ,&nbsp;Lenin González-Paz","doi":"10.1016/j.bpc.2024.107388","DOIUrl":"10.1016/j.bpc.2024.107388","url":null,"abstract":"<div><div>Bacteriocins, a class of molecules produced by bacteria, exhibit potent antimicrobial properties, including antiviral activities. The urgent need for treatments against SARS-CoV-2 has proposed bacteriocins such as enterocin DD14 (EntDD14) as potential therapeutic agents. However, the mechanism of macromolecular interaction of EntDD14 for the inhibition of SARS-CoV-2 is not yet fully understood, and its efficacy against variants like JN.1 has not been completely established. To address these knowledge gaps, biocomputational analyses were employed using a diverse set of tools, including Markov state models and volumetric analyses. This analysis revealed a favorable interaction between EntDD14 and the receptor-binding domain (RBD) of SARS-CoV-2. Furthermore, it was found that EntDD14 induces changes in the flexibility of the RBD and alters the distribution and size of its internal cavities, particularly in the JN.1 variant. These findings align with experimental observations and support the inhibitory mechanism of EntDD14 against SARS-CoV-2. Additionally, they suggest that EntDD14 may possess a broader spectrum of action, encompassing the JN.1 variant. This study paves the way for future investigations and therapeutic applications, encouraging further exploration of the antiviral activity of bacteriocins like EntDD14 against variants of concern like JN.1. However, additional experimental demonstrations are warranted to substantiate these findings.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107388"},"PeriodicalIF":3.3,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143132616","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":"Investigation of serotonin-receptor interactions, stability and signal transduction pathways via molecular dynamics simulations","authors":"Arunima Verma ,&nbsp;Padmabati Mondal","doi":"10.1016/j.bpc.2024.107386","DOIUrl":"10.1016/j.bpc.2024.107386","url":null,"abstract":"<div><div>Serotonin-receptor binding plays a key role in several neurological and biological processes, including mood, sleep, hunger, cognition, learning, and memory. In this article, we performed molecular dynamics simulation to examine the key residues that play an essential role in the binding of serotonin to the G-protein-coupled 5-HT_1<em>B</em> receptor (5HT_1<em>B</em>R) via electrostatic interactions. Key residues for electrostatic interactions were identified via bond distance analysis and frustration analysis methods. An end-point free energy calculation method determines the stability of the 5-HT_1<em>B</em>R due to serotonin binding. The single-point mutation of the polar/charged amino acid residues (Asp129, Thr134) on the binding sites and the calculation of binding free energy validate the quantitative contribution of these residues to the stability of the serotonin-receptor complex. The principal component analysis reflects that the serotonin-bound 5-HT_1<em>B</em>R is more stabilized than the apo-receptor regarding dynamical changes. The difference dynamic cross-correlations map shows the correlation between the transmembranes and mini-G_<em>o</em>, which indicates that the signal transduction happens between mini-G_<em>o</em> and the receptor. Allosteric pathway analysis reveals the key nodes and key pathways for signal transduction in 5-HT_1<em>B</em>R. These results provide useful insights into the study of signal transduction pathways and mutagenesis to regulate the binding and functionality of the complex. The developed protocols can be applied to study local non-covalent interactions and long-range allosteric communications in any protein-ligand system for computer-aided drug design.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107386"},"PeriodicalIF":3.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930649","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":"Cationic liposomes as carriers of natural compounds from plant extract","authors":"Claudia Bonechi ,&nbsp;Gabriella Tamasi ,&nbsp;Alessandro Donati ,&nbsp;Flavia Bisozzi ,&nbsp;Michele Baglioni ,&nbsp;Marco Andreassi ,&nbsp;Francesca Ietta ,&nbsp;Gemma Leone ,&nbsp;Agnese Magnani ,&nbsp;Claudio Rossi","doi":"10.1016/j.bpc.2024.107381","DOIUrl":"10.1016/j.bpc.2024.107381","url":null,"abstract":"<div><div>Lipid-based nanocarriers provide versatile platforms for the encapsulation and delivery of many different bioactive compounds to improve the solubility, stability and therapeutic efficacy of bioactive phyto-compounds. In this study, liposomes were used to load leaf extract of <em>Coffea Arabica</em>, which is known to be rich beneficial substances such as alkaloids, flavonoids, etc. The aim of this work is to optimize the valorization of agricultural wastes containing natural antioxidants. The physico-chemical properties of the liposomes loaded with chlorogenic acid or <em>Coffea arabica</em> leaf extract were evaluated. The average size of empty and loaded liposomes was found to range of 120–150 nm, which is consistent with the fact that the addition of chlorogenic acid or <em>Coffea arabica</em> leaf extract can change the average size of the vesicles without affecting the physicochemical properties of the lipid bilayer, which remain stable systems. A structural and morphological characterization as well as an evaluation of biological properties such as viability in normal human dermal fibroblasts, is also been carried out. The cationic liposomes show a good average size and low polydispersity index values, indicating that the liposomes tend to be monodisperse and therefore stable. In particular, DOPC/DOTAP liposomes generally have better properties than DOPC/DDAB liposomes for use as encapsulation systems for natural plant extracts.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107381"},"PeriodicalIF":3.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902496","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":"Identification and structural characterization of CB1 receptor antagonists: A comprehensive virtual screening and molecular dynamics study of arachidin-2","authors":"Ana C. Murrieta,&nbsp;Paola Mendoza-Espinosa,&nbsp;José Luis Velasco-Bolom,&nbsp;Flavio F. Contreras-Torres","doi":"10.1016/j.bpc.2024.107385","DOIUrl":"10.1016/j.bpc.2024.107385","url":null,"abstract":"<div><div>The cannabinoid receptor 1 (CB1) is an essential component of the endocannabinoid system, responsible for regulating various physiological processes such as pain, mood, and appetite. Despite increasing interest in the therapeutic potential of CB1 modulators, the precise mechanisms by which small molecules modulate receptor activity—particularly without fully transitioning between active and inactive states—remain partially understood. In this study, the complexity of CB1–ligand interactions was evaluated for the inactive CB1 state. A comprehensive pipeline, integrating ligand-based similarity search, 2D fingerprint-based reverse virtual screening and molecular dynamics (MD) simulations, identified compounds with core scaffolds commonly found in bioactive natural products, such as stilbenoids and polyphenolic compounds. Arachidin-2 (AR2) and a polyphenolic derivative were subjected to extended MD simulations, revealing their ability to stabilize the inactive CB1 state across key helices. The distinct stability differences observed in the helices HI, HIV, and HVI of the active CB1 state further highlighted ligand-specific conformational dynamics. A comparative analysis with co-crystallized synthetic ligands AM6538 and AM841 demonstrated the distinct binding behaviors of natural and synthetic ligands. AR2 showed more favorable binding to the inactive form (−22.0 kcal/mol) than to the active state. Similarly, the polyphenolic compound exhibited a greater binding difference (∼6 kcal/mol) between the inactive and active states. Notably, AM6538 and AM841 demonstrated the strongest binding (∼30 kcal/mol) to the inactive and active state, respectively. Key residues stabilizing the identified compounds in CB1-inactive state included PHE102, GLY166, PHE170, VAL196, LEU359, SER383, and CIS386. These findings underscore the utility of computational methods in the discovery and development of novel CB1 modulators for potential biomedical applications.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"318 ","pages":"Article 107385"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891902","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}