ligand interactions
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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 135
Author(s):  
Yanchun Lin ◽  
Michael L. Gross

Metal ions are critical for the biological and physiological functions of many proteins. Mass spectrometry (MS)-based structural proteomics is an ever-growing field that has been adopted to study protein and metal ion interactions. Native MS offers information on metal binding and its stoichiometry. Footprinting approaches coupled with MS, including hydrogen/deuterium exchange (HDX), “fast photochemical oxidation of proteins” (FPOP) and targeted amino-acid labeling, identify binding sites and regions undergoing conformational changes. MS-based titration methods, including “protein–ligand interactions by mass spectrometry, titration and HD exchange” (PLIMSTEX) and “ligand titration, fast photochemical oxidation of proteins and mass spectrometry” (LITPOMS), afford binding stoichiometry, binding affinity, and binding order. These MS-based structural proteomics approaches, their applications to answer questions regarding metal ion protein interactions, their limitations, and recent and potential improvements are discussed here. This review serves as a demonstration of the capabilities of these tools and as an introduction to wider applications to solve other questions.


Author(s):  
Xun Chen ◽  
Wei Lu ◽  
Min-Yeh Tsai ◽  
Shikai Jin ◽  
Peter G. Wolynes

AbstractHeme is an active center in many proteins. Here we explore computationally the role of heme in protein folding and protein structure. We model heme proteins using a hybrid model employing the AWSEM Hamiltonian, a coarse-grained forcefield for the protein chain along with AMBER, an all-atom forcefield for the heme. We carefully designed transferable force fields that model the interactions between the protein and the heme. The types of protein–ligand interactions in the hybrid model include thioester covalent bonds, coordinated covalent bonds, hydrogen bonds, and electrostatics. We explore the influence of different types of hemes (heme b and heme c) on folding and structure prediction. Including both types of heme improves the quality of protein structure predictions. The free energy landscape shows that both types of heme can act as nucleation sites for protein folding and stabilize the protein folded state. In binding the heme, coordinated covalent bonds and thioester covalent bonds for heme c drive the heme toward the native pocket. The electrostatics also facilitates the search for the binding site.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Apurba Paul ◽  
Joshua Alper

AbstractThe non-covalent biological bonds that constitute protein–protein or protein–ligand interactions play crucial roles in many cellular functions, including mitosis, motility, and cell–cell adhesion. The effect of external force ($$F$$ F ) on the unbinding rate ($${k}_{\text{off}}\left(F\right)$$ k off F ) of macromolecular interactions is a crucial parameter to understanding the mechanisms behind these functions. Optical tweezer-based single-molecule force spectroscopy is frequently used to obtain quantitative force-dependent dissociation data on slip, catch, and ideal bonds. However, analyses of this data using dissociation time or dissociation force histograms often quantitatively compare bonds without fully characterizing their underlying biophysical properties. Additionally, the results of histogram-based analyses can depend on the rate at which force was applied during the experiment and the experiment’s sensitivity. Here, we present an analytically derived cumulative distribution function-like approach to analyzing force-dependent dissociation force spectroscopy data. We demonstrate the benefits and limitations of the technique using stochastic simulations of various bond types. We show that it can be used to obtain the detachment rate and force sensitivity of biological macromolecular bonds from force spectroscopy experiments by explicitly accounting for loading rate and noisy data. We also discuss the implications of our results on using optical tweezers to collect force-dependent dissociation data.


2022 ◽  
Author(s):  
Cong Fan ◽  
Xin Wang ◽  
Tianze Wang ◽  
Huiying Zhao

Recent studies suggest RNAs playing essential roles in many cell activities and act as promising drug targets. However, limited development has been achieved in detecting RNA-ligand interactions. To guide the discovery of RNA-binding ligands, it is necessary to characterize them comprehensively. We established a database, RNALID that collects RNA-ligand interactions validated by low-throughput experiment. RNALID contains 358 RNA-ligand interactions. Comparing to other databases, 94.5% of ligands in RNALID are completely or partially novel collections, and 51.78% have novel two-dimensional (2D) structures. The ligand structure analysis indicated that multivalent ligands (MV), ligands binding with cellular mRNA (mRNA), ligands binding with RNA from virus (vRNA) and ligands binding with RNA containing repetitive sequence (rep RNA) are more structurally conserved in both 2D and 3D structures than other ligand types. Binding affinity analysis revealed that interactions between ligands and rep RNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than the interactions between ligands and non-rep RNAs; the interactions between ligands and vRNA were significantly stronger (two-tailed MW-U test P-value = 0.012) than those between ligands and mRNA. Drug-likeness analysis indicated that small molecule (SM) ligands binding with non-rep RNA or vRNA may have higher probability to be drugs than other types of ligands. Comparing ligands in RNALID to FDA-approved drugs and ligands without bioactivity indicated that RNA-binding ligands are different from them in chemical properties, structural properties and drug-likeness. Thus, characterizing the RNA-ligand interactions in RNALID in multiple respects provides new insights into discovering and designing druggable ligands binding with RNA.


2021 ◽  
Author(s):  
Bo Peng ◽  
kun zhang

The availability of a range of excited states has enriched zero-, one- and two- dimensional quantum nanomaterials with interesting luminescence properties, in particular for noble metal nanoclusters (NCs) as typical examples. But, the elucidation and origin of optoelectronic properties remains elusive. In this report, using widely used Au(I)-alkanethiolate complex (Au(I)-SRs, R = -(CH2)12H) with AIE characteristics as a model system, by judiciously manipulating the delicate surface ligand interactions at the nanoscale interface, together with a careful spectral investigations and an isotope diagnostic experiment of heavy water (D2O), we evidenced that the structural water molecules (SWs) confined in the nanoscale interface or space are real emitter centers for photoluminescence (PL) of metal NCs and the aggregate of Au(I)-SRs complexes, instead of well-organized metal core dominated by quantum confinement mechanics. Interestingly, the aggregation of Au(I)-SRs generated dual fluorescence-phosphorescence emission and the photoluminescence intensity was independent on the degree of aggregation but showed strong dependency on the content and state of structural water molecules (SWs) confined in the aggregates. SWs are different from traditional hydrogen bonded water molecules, wherein, due to interfacial adsorption or spatial confinement, the p orbitals of two O atoms in SWs can form a weak electron interaction through spatial overlapping, which concomitantly constructs a group of interfacial states with π bond characteristics, consequently providing some alternative channels (or pathways) to the radiation and/or non-radiation relaxation of electrons. Our results provide completely new insights to understand the fascinating properties (including photoluminescence, catalysis and chirality, etc.) of other low-dimension quantum dots and even for aggregation-induced emission luminophores (AIEgens). This also answers the century old debate on whether and how water molecules emit bright color.


2021 ◽  
Vol 18 (4) ◽  
pp. 801-815
Author(s):  
Meenambiga Setti Sudharsan ◽  
Sandra Jose ◽  
Sowmya Hari ◽  
Venkataraghavan Ragunathan ◽  
Sakthiselvan Punniavan

In the Fatty Acid Synthase II system, Enoyl-(acyl-carrier-protein) reductase (ENR) encoded by FabI genes is a limiting step enzyme and there is no homologue ENR found in invertebrates which makes it selective target for drug discovery. From Molecular dynamics simulations it was concluded that the solvated protein stabilized at 2.5 ns with larger mobility in the substrate - binding loop and the conformational flexibility of the molecule was revealed. To study the inhibitory effects of novel small molecules in the thiopyridine series, a 2D QSAR model was developed and evaluated for its efficiency. The R2 > 0.96 and Q2 = 0.978 depicted the predictive ability of the models which was determined using a test set of 3 compounds. The receptor-ligand interactions were studied and highest affinity was reported for GCT ID, 343129 (-9.09 Kcal/mol), 341772 (-8.90 Kcal/mol) and 268776 (-8.85 Kcal/mol). These compounds were analysed for their drug like properties and toxicity which projected acceptable blood brain barrier permeation and human intestinal absorption and reduced lipotoxicity. Thus the results suggest further synthesis of new thipyridine series of compounds and experimental testing against drug resistant Staphylococcal infections


2021 ◽  
Vol 15 (1) ◽  
pp. 12
Author(s):  
R. N. V. Krishna Deepak ◽  
Ravi Kumar Verma ◽  
Yossa Dwi Hartono ◽  
Wen Shan Yew ◽  
Hao Fan

Great progress has been made over the past decade in understanding the structural, functional, and pharmacological diversity of lipid GPCRs. From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology. The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened our comprehension of the structural and functional facets of the receptor family members and has helped usher in a modern age of structure-based drug design and development. First, we provide a primer on lipid mediators and lipid GPCRs and their role in physiology and diseases as well as their value as drug targets. Second, we summarize the current advancements in the understanding of structural features of lipid GPCRs, such as the structural variation of their extracellular domains, diversity of their orthosteric and allosteric ligand binding sites, and molecular mechanisms of ligand binding. Third, we close by collating the emerging paradigms and opportunities in targeting lipid GPCRs, including a brief discussion on current strategies, challenges, and the future outlook.


Author(s):  
Stephanie E A Burnell ◽  
Lorenzo Capitani ◽  
Bruce J MacLachlan ◽  
Georgina H Mason ◽  
Awen M Gallimore ◽  
...  

Abstract Despite three decades of research to its name and increasing interest in immunotherapies which target it, LAG-3 remains an elusive co-inhibitory receptor in comparison to the well-established PD-1 and CTLA-4. As such, LAG-3 targeting therapies have yet to achieve the clinical success of therapies targeting other checkpoints. This could, in part, be attributed to the many unanswered questions that remain regarding LAG-3 biology. Of these, we (i) the function of the many LAG-3:ligand interactions; (ii) the hurdles that remain to acquire a high resolution structure of LAG-3; (iii) the under-studied LAG-3 signal transduction mechanism; (iv) the elusive soluble form of LAG-3; (v) the implications of the lack of (significant) phenotype of LAG-3 knockout mice; (vi) the reports of LAG-3 expression on epithelium and (vii) the conflicting reports of LAG-3 expression (and potential contributions to pathology) in the brain. These mysteries which surround LAG-3 highlight how the ever-evolving study of its biology continues to reveal ever-increasing complexity in its role as an immune receptor. Importantly, answering the questions which shroud LAG-3 in mystery will allow maximum therapeutic benefit of LAG-3 targeting immunotherapies in cancer, autoimmunity and beyond.


Author(s):  
Mamta Sagar ◽  
Padma Saxena ◽  
Suruchi Singh ◽  
Ravindra Nath ◽  
Pramod W. Ramteke

Molecular docking is an efficient way to study protein-protein and protein-ligand interactions in virtual mode, this provides structural annotations of molecular interactions, required in the drug discovery process. The Cartesian FFT approach in ‘Hex’ spherical polar Fourier (SPF) uses rotational correlations, this method is used here to study protein-protein interactions. Hepatitis B virus (HBV) X protein (HBx) is essential for virus infection and has been used in the development of therapeutics for liver cancer. It can interact with many cellular proteins. It interferes with cell viability and stimulates HBV replication. The von Hippel-Lindau binding protein 1(VBP1) has an important role in HBx-mediated nuclear factor kappa B (NFkB) stimulation. VBP1 and HBx function as coactivators in the activation of NFκB binding. Docking results revealed that HBx and NFkB bind with VBP1 at the common site on amino acids positions Arg 161, Glu 92, and Arg 82, which may have a role in HBx-mediated NFκB activation. Lowest energy complex VBP1- NFkB1 was obtained at -883.70 Kcal/mol. The amino acids involved in interaction among HBx, VBP1, and NFκB proteins, may be involved in transcriptional regulation and has significance in normal and abnormal regulation. These amino acid interactions may be associated with the manifestation of Liver cancer.


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