Biophysica最新文献_第6页

Structural Analysis of Interactions between Epidermal Growth Factor Receptor (EGFR) Mutants and Their Inhibitors 表皮生长因子受体(EGFR)突变体及其抑制剂相互作用的结构分析

Biophysica Pub Date : 2023-03-14 DOI: 10.3390/biophysica3010013

Yingzhe Guo, Zeqian Du, Ting Shi

{"title":"Structural Analysis of Interactions between Epidermal Growth Factor Receptor (EGFR) Mutants and Their Inhibitors","authors":"Yingzhe Guo, Zeqian Du, Ting Shi","doi":"10.3390/biophysica3010013","DOIUrl":"https://doi.org/10.3390/biophysica3010013","url":null,"abstract":"People’s lives and health are gravely threatened by non-small-cell lung cancer (NSCLC). Mutations in epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase, are considered one of the causes of NSCLC. Tyrosine kinase inhibitors (TKIs) are typically used to treat patients with EGFR mutations. In this study, Gefitinib, a member of the first generation of TKIs, was used to treat an EGFR single-point mutation (single mutant, SM). Patients harboring additional T790M mutations in the kinase domain of the EGFR were resistant to Gefitinib. Then, the L858R/T790M double mutation (double mutant, DM) was treated with the second generation of TKIs, such as Afatinib. Here, we constructed four computational models to uncover the structural basis between EGFR mutants (SM and DM) and corresponding inhibitors (Gefitinib and Afatinib). The binding energy in the G-SM (representing Gefitinib in complex with SM) system was larger than that in the G-DM (Representing Gefitinib in complex with DM) system. Gefitinib’s affinity with L792 and M793 was drastically reduced by the longer side chain of M790 in the G-DM system, which pushed Gefitinib outside of the pocket. Additionally, the A-DM system’s binding energy was higher than the G-DM system’s. Afatinib, unlike Gefitinib, induced the P-loop region to move downwards to decrease the pocket entrance size to accommodate Afatinib properly and stably in the A-DM (Afatinib in complex with DM) system. These results uncover the details of interactions between EGFR and its inhibitors and shed light on the design of new tyrosine kinase inhibitors.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46652936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Neuronal Cultures: Exploring Biophysics, Complex Systems, and Medicine in a Dish 神经元培养:探索生物物理学，复杂系统和医学在一个盘子

Biophysica Pub Date : 2023-03-10 DOI: 10.3390/biophysica3010012

J. Soriano

引用次数: 1

A Brief Review of FT-IR Spectroscopy Studies of Sphingolipids in Human Cells 人细胞鞘磷脂的FT-IR光谱研究综述

Biophysica Pub Date : 2023-03-02 DOI: 10.3390/biophysica3010011

B. Faramarzi, M. Moggio, N. Diano, M. Portaccio, M. Lepore

引用次数: 3

Insights into the Substrate Uptake Mechanism of Mycobacterium Tuberculosis Ribose 5-Phosphate Isomerase and Perspectives on Drug Development 结核分枝杆菌5-磷酸核糖异构酶底物摄取机制研究及药物开发展望

Biophysica Pub Date : 2023-03-01 DOI: 10.3390/biophysica3010010

L. Bartkevihi, Í. Caruso, Bruna Martins, J. Pires, D. Oliveira, C. D. Anobom, Fábio Luz Almeida

{"title":"Insights into the Substrate Uptake Mechanism of Mycobacterium Tuberculosis Ribose 5-Phosphate Isomerase and Perspectives on Drug Development","authors":"L. Bartkevihi, Í. Caruso, Bruna Martins, J. Pires, D. Oliveira, C. D. Anobom, Fábio Luz Almeida","doi":"10.3390/biophysica3010010","DOIUrl":"https://doi.org/10.3390/biophysica3010010","url":null,"abstract":"The active site of the dimeric ribose 5-phosphate isomerase B (RpiB) contains a solvent-exposed barrier formed by residues H12, R113, R137, and R141, which is closed upon the complexation of phosphate. The substrate ribose 5-phosphate (R5P) has to overcome the surface barrier to reach an internal cavity and then bind in the linear configuration of ribose to the interface between the two subunits. NMR and molecular dynamics simulation are suitable methods to describe the transient nature of the RpiB active site and help our understanding of the mechanism of substrate entrance. In this study, we show that the entrance of the nucleotides AMP/ADP into the internal cavity of mycobacterium tuberculosis RpiB (MtRpiB) does not involve a canonical open/close-lid conformational transition usually observed in many enzymes. Instead, a flipping mechanism in which the nucleotide phosphate interacts with the surface barrier followed by the flip of the nitrogenous base and ribose is responsible for changing the substrate/ligand orientation from a solvent-exposed to a buried state. Based on these results, we propose a substrate/inhibitor uptake mechanism that could provide a basis for rational drug design using MtRpiB, which is an essential enzyme and a good target for drug development.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46621081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigation of the Impact of Lipid Acyl Chain Saturation on Fusion Peptide Interactions with Lipid Bilayers 脂质酰链饱和对融合肽与脂质双层相互作用的影响研究

Biophysica Pub Date : 2023-02-28 DOI: 10.3390/biophysica3010009

W. T. Heller, P. Zolnierczuk

{"title":"Investigation of the Impact of Lipid Acyl Chain Saturation on Fusion Peptide Interactions with Lipid Bilayers","authors":"W. T. Heller, P. Zolnierczuk","doi":"10.3390/biophysica3010009","DOIUrl":"https://doi.org/10.3390/biophysica3010009","url":null,"abstract":"The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45586624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The Effectiveness of Suffruticosol B in Treating Lung Cancer by the Laser Trapping Technique Suffruticosol B激光捕捉技术治疗肺癌癌症的疗效

Biophysica Pub Date : 2023-02-13 DOI: 10.3390/biophysica3010008

Mulugeta S. Goangul, Rance Solomon, Daniel Devito, C. Brown, J. Coopper, D. Erenso, Ying Gao, Aline Pellizzaro, Jennifer M. Revalee, H. Crogman

引用次数: 0

Contribution of smFRET to Chromatin Research smFRET对染色质研究的贡献

Biophysica Pub Date : 2023-02-08 DOI: 10.3390/biophysica3010007

B. Sengupta, Mai T Huynh

引用次数: 0

Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease 黄病毒NS2B–NS3蛋白酶可塑性的结构观察及黄酮类变构抑制剂的发现

Biophysica Pub Date : 2023-02-01 DOI: 10.3390/biophysica3010006

M. Saivish, G. Menezes, Vaston Gonçalves da Costa, Liliane Nebo, G. C. D. Silva, C. Pacca, R. E. Marques, M. Nogueira, R. D. da Silva

{"title":"Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease","authors":"M. Saivish, G. Menezes, Vaston Gonçalves da Costa, Liliane Nebo, G. C. D. Silva, C. Pacca, R. E. Marques, M. Nogueira, R. D. da Silva","doi":"10.3390/biophysica3010006","DOIUrl":"https://doi.org/10.3390/biophysica3010006","url":null,"abstract":"Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases in developing countries but are not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins are encoded in the flavivirus RNA. The N2B–NS3pro protein complex plays a fundamental role in flavivirus replication and is a promising drug target; however, no flavivirus protease inhibitors have progressed to the preclinical stage. This study analyzed the structural models and plasticity of the NS2B–NS3pro protein complex of five medically important non-dengue flaviviruses (West Nile, Rocio, Ilhéus, yellow fever, and Saint Louis encephalitis). The flavonoids amentoflavone, tetrahydrorobustaflavone, and quercetin were selected for their exceptional binding energies as potential inhibitors of the NS2B–NS3pro protein complex. AutoDock Vina results ranged from −7.0 kcal/mol to −11.5 kcal/mol and the compounds preferentially acted non-competitively. Additionally, the first structural model for the NS2B–NS3pro protein complex was proposed for Ilhéus and Rocio viruses. The NS2B–NS3pro protease is an attractive molecular target for drug development. The three identified natural flavonoids showed great inhibitory potential against the viral species. Nevertheless, further in silico and in vitro studies are required to obtain more information regarding NS2B–NS3pro inhibition by these flavonoids and their therapeutic potential.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42559415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Acknowledgment to the Reviewers of Biophysica in 2022 感谢2022年《生物物理学》审稿人

Biophysica Pub Date : 2023-01-28 DOI: 10.3390/biophysica3010005

引用次数: 0

Effect of the Neck Linker on Processive Stepping of Kinesin Motor 连杆颈对Kinesin电机步进过程的影响

Biophysica Pub Date : 2023-01-28 DOI: 10.3390/biophysica3010004

P. Xie

{"title":"Effect of the Neck Linker on Processive Stepping of Kinesin Motor","authors":"P. Xie","doi":"10.3390/biophysica3010004","DOIUrl":"https://doi.org/10.3390/biophysica3010004","url":null,"abstract":"Kinesin motor protein, which is composed of two catalytic domains connected together by a long coiled-coil stalk via two flexible neck linkers (NLs), can step processively on a microtubule towards the plus end by hydrolyzing adenosine triphosphate (ATP) molecules. To understand what the role is that the NL plays in the processive stepping, the dynamics of the kinesin motor are studied theoretically here by considering the mutation or deletion of an N-terminal cover strand that contributes to the docking of the NL in kinesin-1, the extension of the NL in kinesin-1, the mutation of the NL in kinesin-1, the swapping of the NL of kinesin-2 with that of kinesin-1, the joining of the stalk and neck of Ncd that moves towards the minus end of MT to the catalytic domain of kinesin-1, the replacement of catalytic domain of kinesin-1 with that of Ncd, and so on. The theoretical results give a consistent and quantitative explanation of various available experimental results about the effects of these mutations on motor dynamics and, moreover, provide predicted results. Additionally, the processive motility of kinesin-6 MKLP2 without NL docking is also explained. The available experimental data about the effect of NL mutations on the dynamics of the bi-directional kinesin-5 Cin8 are also explained. The studies are critically implicative to the mechanism of the stepping of the kinesin motor.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49061738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0