Current Research in Structural Biology最新文献

{"title":"GraSp-PSN: A web server for graph spectra based analysis of protein structure networks","authors":"Vasundhara Gadiyaram,&nbsp;Vasam Manjveekar Prabantu,&nbsp;Arinnia Anto Manjaly ,&nbsp;Ananth Muthiah,&nbsp;Saraswathi Vishveshwara","doi":"10.1016/j.crstbi.2024.100147","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100147","url":null,"abstract":"<div><p>The function of a protein is most of the time achieved due to minute conformational changes in its structure due to ligand binding or environmental changes or other interactions. Hence the analysis of structure of proteins should go beyond the analysis of mere atom contacts and should include the emergent global structure as a whole. This can be achieved by graph spectra based analysis of protein structure networks. GraSp-PSN is a web server that can assist in (1) acquiring weighted protein structure network (PSN) and network parameters ranging from atomic level to global connectivity from the three dimensional coordinates of a protein, (2) generating scores for comparison of a pair of protein structures with detailed information of local to global connectivity, and (3) assigning perturbation scores to the residues and their interactions, that can prioritise them in terms of residue clusters. The methods implemented in the server are generic in nature and can be used for comparing networks in any discipline by uploading adjacency matrices in the server. The webserver can be accessed using the following link: <span>https://pople.mbu.iisc.ac.in/</span><svg><path></path></svg>.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100147"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000242/pdfft?md5=739c6cab73a5919caa6cedc6fe5317c7&pid=1-s2.0-S2665928X24000242-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140879520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and function of the light-protective orange carotenoid protein families","authors":"Teresa M. García-Oneto ,&nbsp;Claudia Moyano-Bellido ,&nbsp;M. Agustina Domínguez-Martín","doi":"10.1016/j.crstbi.2024.100141","DOIUrl":"10.1016/j.crstbi.2024.100141","url":null,"abstract":"<div><p>Orange carotenoid proteins (OCPs) are unique photoreceptors that are critical for cyanobacterial photoprotection. Upon exposure to blue-green light, OCPs are activated from a stable orange form, OCP^O, to an active red form, OCP^R, which binds to phycobilisomes (PBSs) and performs photoprotective non-photochemical quenching (NPQ). OCPs can be divided into three main families: the most abundant and best studied OCP1, and two others, OCP2 and OCP3, which have different activation and quenching properties and are yet underexplored. Crystal structures have been acquired for the three OCP clades, providing a glimpse into the conformational underpinnings of their light-absorption and energy dissipation attributes. Recently, the structure of the PBS-OCP^R complex has been obtained allowing for an unprecedented insight into the photoprotective action of OCPs. Here, we review the latest findings in the field that have substantially improved our understanding of how cyanobacteria protect themselves from the toxic consequences of excess light absorption. Furthermore, current research is applying the structure of OCPs to bio-inspired optogenetic tools, to function as carotenoid delivery devices, as well as engineering the NPQ mechanism of cyanobacteria to enhance their photosynthetic biomass production.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100141"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000187/pdfft?md5=94fcdc3bbbf23bc37abf0f283dfea5e5&pid=1-s2.0-S2665928X24000187-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140757478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternate conformations found in protein structures implies biological functions: A case study using cyclophilin A","authors":"Chandrasekaran Palaniappan ,&nbsp;Santhosh Rajendran ,&nbsp;Kanagaraj Sekar","doi":"10.1016/j.crstbi.2024.100145","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100145","url":null,"abstract":"<div><p>Protein dynamics linked to numerous biomolecular functions, such as ligand binding, allosteric regulation, and catalysis, must be better understood at the atomic level. Reactive atoms of key residues drive a repertoire of biomolecular functions by flipping between alternate conformations or conformational substates, seldom found in protein structures. Probing such sparsely sampled alternate conformations would provide mechanistic insight into many biological functions. We are therefore interested in evaluating the instance of amino acids adopted alternate conformations, either in backbone or side-chain atoms or in both. Accordingly, over 70000 protein structures appear to contain alternate conformations only 'A' and 'B' for any atom, particularly the instance of amino acids that adopted alternate conformations are more for Arg, Cys, Met, and Ser than others. The resulting protein structure analysis depicts that amino acids with alternate conformations are mainly found in the helical and β-regions and are often seen in high-resolution X-ray crystal structures. Furthermore, a case study on human cyclophilin A (CypA) was performed to explain the pre-existing intrinsic dynamics of catalytically critical residues from the CypA and how such intrinsic dynamics perturbed upon Ser99Thr mutation using molecular dynamics simulations on the ns-μs timescale. Simulation results demonstrated that the Ser99Thr mutation had impaired the alternate conformations or the catalytically productive micro-environment of Phe113, mimicking the experimentally observed perturbation captured by X-ray crystallography. In brief, a deeper comprehension of alternate conformations adopted by the amino acids may shed light on the interplay between protein structure, dynamics, and function.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100145"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000229/pdfft?md5=99f78944ded3d8b7139bf3f324f58946&pid=1-s2.0-S2665928X24000229-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140638479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of coumarin derivatives targeting acetylcholinesterase for Alzheimer's disease by field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, MM/GBSA, ADME and MD Simulation study","authors":"Bikram Saha ,&nbsp;Agnidipta Das ,&nbsp;Kailash Jangid ,&nbsp;Amit Kumar ,&nbsp;Vinod Kumar ,&nbsp;Vikas Jaitak","doi":"10.1016/j.crstbi.2024.100124","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100124","url":null,"abstract":"<div><p>Alzheimer's disease (AD) leads to gradual memory loss including other compromised cognitive abilities. Acetylcholinesterase (AChE), an important biochemical enzyme from the cholinesterase (ChE) family, is recognized as primary pharmacological target for treating AD. Currently marketed drugs for AD treatment are primarily AChE inhibitors and coumarin derivatives comprising a wide variety of pharmacological activities have proved their efficacy towards AChE inhibition. Ensaculin (KA-672 HCl), a compound that belong to the coumarin family, is a clinical trial candidate for AD treatment. Therefore, a ligand library was prepared with 60 reported coumarin derivatives for field-based 3D-QSAR and pharmacophore modelling. The field-based 3D-QSAR model obtained at partial least square (PLS) factor 7, was the best validated model that predicted activity closer to original activity for each ligand introduced. The contour maps demonstrated spatial distribution of favourable and unfavorable steric, hydrophobic, electrostatic and H-bond donor and acceptor contours around coumarin nucleus. The best pharmacophore model, ADHRR_1 exhibited five essential pharmacophoric features of four different traits for optimum AChE inhibition. Virtual screening through ADHRR_1 accompanied with molecular docking and MM/GBSA identified 10 HITs from a 4,00,000 coumarin derivatives from PubChem database. HITs comprised docking scores ranging from −12.096 kcal/mol to −8.271 kcal/mol and compared with the reference drug Donepezil (-8.271 kcal/mol). ADME properties analysis led into detecting two leads (HIT 1 and HIT 2) among these 10 HITs. Molecular Dynamics Simulation indicated thermodynamic stability of the complex of lead compounds with AChE protein. Finally, thorough survey of the experimental results from 3D-QSAR modelling, pharmacophore modelling and molecular docking interactions led us to develop the lead formula I for future advancements in treating AD through AChE inhibitors.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100124"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000011/pdfft?md5=0302117bf96bd14c51a89e51e6661f84&pid=1-s2.0-S2665928X24000011-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Back in time to the Gly-rich prototype of the phosphate binding elementary function","authors":"Zejun Zheng ,&nbsp;Alexander Goncearenco ,&nbsp;Igor N. Berezovsky","doi":"10.1016/j.crstbi.2024.100142","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100142","url":null,"abstract":"<div><p>Binding of nucleotides and their derivatives is one of the most ancient elementary functions dating back to the Origin of Life. We review here the works considering one of the key elements in binding of (di)nucleotide-containing ligands – phosphate binding. We start from a brief discussion of major participants, conditions, and events in prebiotic evolution that resulted in the Origin of Life. Tracing back to the basic functions, including metal and phosphate binding, and, potentially, formation of primitive protein-protein interactions, we focus here on the phosphate binding. Critically assessing works on the structural, functional, and evolutionary aspects of phosphate binding, we perform a simple computational experiment reconstructing its most ancient and generic sequence prototype. The profiles of the phosphate binding signatures have been derived in form of position-specific scoring matrices (PSSMs), their peculiarities depending on the type of the ligands have been analyzed, and evolutionary connections between them have been delineated. Then, the apparent prototype that gave rise to all relevant phosphate-binding signatures had also been reconstructed. We show that two major signatures of the phosphate binding that discriminate between the binding of dinucleotide- and nucleotide-containing ligands are GxGxxG and GxxGxG, respectively. It appears that the signature archetypal for dinucleotide-containing ligands is more generic, and it can frequently bind phosphate groups in nucleotide-containing ligands as well. The reconstructed prototype's key signature GxGGxG underlies the role of glycine residues in providing flexibility and interactions necessary for binding the phosphate groups. The prototype also contains other ancient amino acids, valine, and alanine, showing versatility towards evolutionary design and functional diversification.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100142"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000199/pdfft?md5=3f93caa1ca09a9390f663f5d40a561d9&pid=1-s2.0-S2665928X24000199-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140555717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular forces driving protein complexation of lentil and whey proteins: Structure-function relationships of trehalose-conjugated protein complexes on protein digestibility and solubility","authors":"Mohammad Alrosan ,&nbsp;Ali Madi Almajwal ,&nbsp;Ali Al-Qaisi ,&nbsp;Sana Gammoh ,&nbsp;Muhammad H. Alu'datt ,&nbsp;Farah R. Al Qudsi ,&nbsp;Thuan-Chew Tan ,&nbsp;Ammar A. Razzak Mahmood ,&nbsp;Sofyan Maghaydah","doi":"10.1016/j.crstbi.2024.100135","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100135","url":null,"abstract":"<div><p>Plant-based proteins are often associated with a range of health benefits. Most research primarily investigates pea and soy proteins, while lentil proteins received minimal attention. This study evaluates the effect of protein complexation (using the pH-shifting technique) coupled with trehalose conjugation on lentil and whey proteins. The protein structures after the modification were analysed using spectroscopic methods: Fourier-transform infrared, ultraviolet spectra, and fluorescence spectra. The amide group I, conformation protein, and tertiary structure of the trehalose-conjugated lentil-whey protein complexes (T-LWPs) showed significant changes (<em>P &lt;</em> 0.05). Moreover, the surface properties (surface hydrophobicity and charges) of T-LWPs were significantly modified (<em>P &lt;</em> 0.05), from 457 to 324 a.u and from 36 to −40 mV, respectively. Due to these modifications on the protein structures, the protein digestibility (80–86%) and water solubility (90–94.5%) of T-LWPs increased significantly (<em>P</em> &lt; 0.05) with the increase in the trehalose concentration, from 0 (control) to 5% (w/w), respectively. This study suggested that coupling protein complexation and trehalose conjugation can enhance the overall properties of lentil-based protein complexes. With this enhancement, more opportunities in the utilisation of lentils are to be expected.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100135"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000126/pdfft?md5=5f24957755903c9c4bf2e15e12650a4f&pid=1-s2.0-S2665928X24000126-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140135101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANN based prediction of ligand binding sites outside deep cavities to facilitate drug designing","authors":"Kalpana Singh,&nbsp;Yashpal Singh Malik","doi":"10.1016/j.crstbi.2024.100144","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100144","url":null,"abstract":"<div><p>The ever-changing environmental conditions and pollution are the prime reasons for the onset of several emerging and re-merging diseases. This demands the faster designing of new drugs to curb the deadly diseases in less waiting time to cure the animals and humans. Drug molecules interact with only protein surface on specific locations termed as ligand binding sites (LBS). Therefore, the knowledge of LBS is required for rational drug designing. Existing geometrical LBS prediction methods rely on search of cavities based on the fact that 83% of the LBS found in deep cavities, however, these methods usually fail where LBS localize outside deep cavities. To overcome this challenge, the present work provides an artificial neural network (ANN) based method to predict LBS outside deep cavities in animal proteins including human to facilitate drug designing. In the present work a feed-forward backpropagation neural network was trained by utilizing 38 structural, atomic, physiochemical, and evolutionary discriminant features of LBS and non-LBS residues localized in the extracted roughest patch on protein surface. The performance of this ANN based prediction method was found 76% better for those proteins where cavity subspace (extracted by MetaPocket 2.0, a consensus method) failed to predict LBS due to their localization outside the deep cavities. The prediction of LBS outside deep cavities will facilitate in drug designing for the proteins where it is not possible due to lack of LBS information as the geometrical LBS prediction methods rely on extraction of deep cavities.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100144"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000217/pdfft?md5=6488d8469a0b3dff9732a9f2ecb71a87&pid=1-s2.0-S2665928X24000217-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140606935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of SARS-CoV-2 spike mutation on peptide presentation is HLA allomorph-specific","authors":"You Min Ahn ,&nbsp;Janesha C. Maddumage ,&nbsp;Emma J. Grant ,&nbsp;Demetra S.M. Chatzileontiadou ,&nbsp;W.W.J. Gihan Perera ,&nbsp;Brian M. Baker ,&nbsp;Christopher Szeto ,&nbsp;Stephanie Gras","doi":"10.1016/j.crstbi.2024.100148","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100148","url":null,"abstract":"<div><p>CD8⁺ T cells are crucial for viral elimination and recovery from viral infection. Nonetheless, the current understanding of the T cell response to SARS-CoV-2 at the antigen level remains limited. The Spike protein is an external structural protein that is prone to mutations, threatening the efficacy of current vaccines. Therefore, we have characterised the immune response towards the immunogenic Spike-derived peptide (S_976-984, VLNDILSRL), restricted to the HLA-A*02:01 molecule, which is mutated in both Alpha (S982A) and Omicron BA.1 (L981F) variants of concern. We determined that the mutation in the Alpha variant (S982A) impacted both the stability and conformation of the peptide, bound to HLA-A*02:01, in comparison to the original S_976-984. We identified a longer and overlapping immunogenic peptide (S_975-984, SVLNDILSRL) that could be presented by HLA-A*02:01, HLA-A*11:01 and HLA-B*13:01 allomorphs. We showed that S975-specific CD8⁺ T cells were weakly cross-reactive to the mutant peptides despite their similar conformations when presented by HLA-A*11:01. Altogether, our results show that the impact of SARS-CoV-2 mutations on peptide presentation is HLA allomorph-specific, and that post vaccination there are T cells able to react and cross-react towards the variant of concern peptides.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100148"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000254/pdfft?md5=68e3219bc99c70680b9c5efa9ff8b0ce&pid=1-s2.0-S2665928X24000254-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140824840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional insights of sortases and their interactions with antivirulence compounds","authors":"Sowmiya Sri Sivaramalingam ,&nbsp;Deepsikha Jothivel ,&nbsp;Deenadayalan Karaiyagowder Govindarajan ,&nbsp;Lohita Kadirvelu ,&nbsp;Muthusaravanan Sivaramakrishnan ,&nbsp;Dhivia Dharshika Chithiraiselvan ,&nbsp;Kumaravel Kandaswamy","doi":"10.1016/j.crstbi.2024.100152","DOIUrl":"10.1016/j.crstbi.2024.100152","url":null,"abstract":"<div><p>Sortase proteins play a crucial role as integral membrane proteins in anchoring bacterial surface proteins by recognizing them through a Cell-Wall Sorting (CWS) motif and cleaving them at specific sites before initiating pilus assembly. Both sortases and their substrate proteins are major virulence factors in numerous Gram-positive pathogens, making them attractive targets for antimicrobial intervention. Recognizing the significance of virulence proteins, a comprehensive exploration of their structural and functional characteristics is essential to enhance our understanding of pilus assembly in diverse Gram-positive bacteria. Therefore, this review article discusses the structural features of different classes of sortases and pilin proteins, primarily serving as substrates for sortase-assembled pili. Moreover, it thoroughly examines the molecular-level interactions between sortases and their inhibitors, providing insights from both structural and functional perspectives. In essence, this review article will provide a contemporary and complete understanding of both sortase pathways and various strategies to target them effectively to counteract the virulence.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"8 ","pages":"Article 100152"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000291/pdfft?md5=db64ca05515c00e67922cda0b3897a38&pid=1-s2.0-S2665928X24000291-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141395433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane binding and lipid-protein interaction of the C2 domain from coagulation factor V","authors":"Y. Zenmei Ohkubo ,&nbsp;Peter W. Radulovic ,&nbsp;Albert N. Kahira ,&nbsp;Jesper J. Madsen","doi":"10.1016/j.crstbi.2024.100149","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100149","url":null,"abstract":"<div><p>Anchoring of coagulation factors to anionic regions of the membrane involves the C2 domain as a key player. The rate of enzymatic reactions of the coagulation factors is increased by several orders of magnitude upon membrane binding. However, the precise mechanisms behind the rate acceleration remain unclear, primarily because of a lack of understanding of the conformational dynamics of the C2-containing factors and corresponding complexes. We elucidate the membrane-bound form of the C2 domain from human coagulation factor V (FV–C2) by characterizing its membrane binding the specific lipid-protein interactions. Employing all-atom molecular dynamics simulations and leveraging the highly mobile membrane-mimetic (HMMM) model, we observed spontaneous binding of FV-C2 to a phosphatidylserine (PS)-containing membrane within 2–25 ns across twelve independent simulations. FV-C2 interacted with the membrane through three loops (spikes 1–3), achieving a converged, stable orientation. Multiple HMMM trajectories of the spontaneous membrane binding provided extensive sampling and ample data to examine the membrane-induced effects on the conformational dynamics of C2 as well as specific lipid-protein interactions. Despite existing crystal structures representing presumed “open” and “closed” states of FV-C2, our results revealed a continuous distribution of structures between these states, with the most populated structures differing from both “open” and “closed” states observed in crystal environments. Lastly, we characterized a putative PS-specific binding site formed by K23, Q48, and S78 located in the groove enclosed by spikes 1–3 (PS-specificity pocket), suggesting a different orientation of a bound headgroup moiety compared to previous proposals based upon analysis of static crystal structures.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100149"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000266/pdfft?md5=e8ab6e6a13338f75043488820ca37b17&pid=1-s2.0-S2665928X24000266-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140879519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}