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Biophysical Journal May 2019Rebinding kinetics of molecular ligands plays a key role in the operation of biomachinery, from regulatory networks to protein transcription, and is also a key factor in...
Rebinding kinetics of molecular ligands plays a key role in the operation of biomachinery, from regulatory networks to protein transcription, and is also a key factor in design of drugs and high-precision biosensors. In this study, we investigate initial release and rebinding of ligands to their binding sites grafted on a planar surface, a situation commonly observed in single-molecule experiments and that occurs in vivo, e.g., during exocytosis. Via scaling arguments and molecular dynamic simulations, we analyze the dependence of nonequilibrium rebinding kinetics on two intrinsic length scales: the average separation distance between the binding sites and the total diffusible volume (i.e., height of the experimental reservoir in which diffusion takes place or average distance between receptor-bearing surfaces). We obtain time-dependent scaling laws for on rates and for the cumulative number of rebinding events. For diffusion-limited binding, the (rebinding) on rate decreases with time via multiple power-law regimes before the terminal steady-state (constant on-rate) regime. At intermediate times, when particle density has not yet become uniform throughout the diffusible volume, the cumulative number of rebindings exhibits a novel, to our knowledge, plateau behavior because of the three-dimensional escape process of ligands from binding sites. The duration of the plateau regime depends on the average separation distance between binding sites. After the three-dimensional diffusive escape process, a one-dimensional diffusive regime describes on rates. In the reaction-limited scenario, ligands with higher affinity to their binding sites (e.g., longer residence times) delay entry to the power-law regimes. Our results will be useful for extracting hidden timescales in experiments such as kinetic rate measurements for ligand-receptor interactions in microchannels, as well as for cell signaling via diffusing molecules.
Topics: Binding Sites; Diffusion; Kinetics; Ligands; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Proteins
PubMed: 31029377
DOI: 10.1016/j.bpj.2019.02.033 -
Journal of Biomolecular Structure &... Jul 2020Protein structures are highly dynamic macromolecules. This dynamics is often analysed through experimental and/or computational methods only for an isolated or a limited...
Protein structures are highly dynamic macromolecules. This dynamics is often analysed through experimental and/or computational methods only for an isolated or a limited number of proteins. Here, we explore large-scale protein dynamics simulation to observe dynamics of local protein conformations using different perspectives. We analysed molecular dynamics to investigate protein flexibility locally, using classical approaches such as RMSf, solvent accessibility, but also innovative approaches such as local entropy. First, we focussed on classical secondary structures and analysed specifically how β-strand, β-turns, and bends evolve during molecular simulations. We underlined interesting specific bias between β-turns and bends, which are considered as the same category, while their dynamics show differences. Second, we used a structural alphabet that is able to approximate every part of the protein structures conformations, namely protein blocks (PBs) to analyse (i) how each initial local protein conformations evolve during dynamics and (ii) if some exchange can exist among these PBs. Interestingly, the results are largely complex than simple regular/rigid and coil/flexible exchange. Abbreviationsnumber of equivalentPBProtein BlocksPDBProtein DataBankRMSfroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.
Topics: Entropy; Molecular Dynamics Simulation; Protein Conformation; Protein Structure, Secondary; Proteins
PubMed: 31361191
DOI: 10.1080/07391102.2019.1650112 -
Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions.Biomolecules Sep 2021Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain... (Review)
Review
Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain dynamic even in specific complexes and functional assemblies. Computer simulations are essential for deriving a molecular description of the disordered protein ensembles and dynamic interactions for a mechanistic understanding of IDPs in biology, diseases, and therapeutics. Here, we provide an in-depth review of recent advances in the multi-scale simulation of disordered protein states, with a particular emphasis on the development and application of advanced sampling techniques for studying IDPs. These techniques are critical for adequate sampling of the manifold functionally relevant conformational spaces of IDPs. Together with dramatically improved protein force fields, these advanced simulation approaches have achieved substantial success and demonstrated significant promise towards the quantitative and predictive modeling of IDPs and their dynamic interactions. We will also discuss important challenges remaining in the atomistic simulation of larger systems and how various coarse-grained approaches may help to bridge the remaining gaps in the accessible time- and length-scales of IDP simulations.
Topics: Humans; Intrinsically Disordered Proteins; Molecular Dynamics Simulation; Protein Conformation
PubMed: 34680048
DOI: 10.3390/biom11101416 -
International Journal of Molecular... Oct 2022This study explored the mechanisms by which the stability of super-secondary structures of the 3β-corner type autonomously outside the protein globule are maintained in...
This study explored the mechanisms by which the stability of super-secondary structures of the 3β-corner type autonomously outside the protein globule are maintained in an aqueous environment. A molecular dynamic (MD) study determined the behavioral diversity of a large set of non-homologous 3β-corner structures of various origins. We focused on geometric parameters such as change in gyration radius, solvent-accessible area, major conformer lifetime and torsion angles, and the number of hydrogen bonds. Ultimately, a set of 3β-corners from 330 structures was characterized by a root mean square deviation (RMSD) of less than 5 Å, a change in the gyration radius of no more than 5%, and the preservation of amino acid residues positioned within the allowed regions on the Ramachandran map. The studied structures retained their topologies throughout the MD experiments. Thus, the 3β-corner structure was found to be rather stable per se in a water environment, i.e., without the rest of a protein molecule, and can act as the nucleus or "ready-made" building block in protein folding. The 3β-corner can also be considered as an independent object for study in field of structural biology.
Topics: Amino Acids; Molecular Dynamics Simulation; Protein Structure, Secondary; Solvents; Water
PubMed: 36232976
DOI: 10.3390/ijms231911674 -
Molecular Informatics Sep 2016In the last decade, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted a great deal of attention being recognized as key regulator of immunosuppressive pathways in the...
In the last decade, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted a great deal of attention being recognized as key regulator of immunosuppressive pathways in the tumor immuno-editing process. Several classes of inhibitors have been developed as potential anticancer agents, but only few of them have advanced in clinical trials. Hence, the quest of novel potent and selective inhibitors of the enzyme is still active and mostly pursued by structure-based drug design strategies based on early and more recent crystal structures of IDO1. Combining docking studies and molecular dynamic simulations, in this work we have comparatively investigated the structural features of each crystal structure of IDO1. The results pinpoint different features in specific crystal structures of the enzyme that may benefit the medicinal chemistry arena aiding the design of novel potent and selective inhibitors of IDO1.
Topics: Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Molecular Docking Simulation; Molecular Dynamics Simulation; Structure-Activity Relationship
PubMed: 27546049
DOI: 10.1002/minf.201501038 -
Current Opinion in Structural Biology Dec 2023Biomolecules exhibit dynamic behavior that single-state models of their structures cannot fully capture. We review some recent advances for investigating multiple... (Review)
Review
Biomolecules exhibit dynamic behavior that single-state models of their structures cannot fully capture. We review some recent advances for investigating multiple conformations of biomolecules, including experimental methods, molecular dynamics simulations, and machine learning. We also address the challenges associated with representing single- and multiple-state models in data archives, with a particular focus on NMR structures. Establishing standardized representations and annotations will facilitate effective communication and understanding of these complex models to the broader scientific community.
Topics: Proteins; Molecular Conformation; Molecular Dynamics Simulation; Magnetic Resonance Spectroscopy; Protein Conformation
PubMed: 37776602
DOI: 10.1016/j.sbi.2023.102703 -
Journal of Biomolecular Structure &... Mar 2022In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which...
In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which killed thousands of people worldwide. Therefore, the necessity to find out the potential therapeutic pharmaceuticals is imperious. This study investigates the inhibitory effect of SARS-CoV-2 3-chymotrypsin-like protease (3CL) using caffeine and caffeine-containing pharmaceuticals (3CPs) based on molecular dynamics simulations and free energy calculations by means of molecular mechanics-Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics-generalized-Born surface area (MMGBSA). Of these 3CPs, seven drugs approved by the US-Food and Drug Administration have shown a good binding affinity to the catalytic residues of 3CL of His and Cys: caffeine, theophylline, dyphylline, pentoxifylline, linagliptin, bromotheophylline and istradefylline. Their binding affinity score ranged from -4.9 to -8.6 kcal/mol. The molecular dynamic simulation in an aqueous solution of docked complexes demonstrated that the 3CPs conformations bound to the active sites of 3CL during 200 ns molecular dynamics simulations. The free energy of binding also confirms the stability of the 3CPs-3CL complexes. To our knowledge, this study shows for the first time very inexpensive drugs available in large quantities that can be potential inhibitors against 3CL. In particular, the repurposing of linagliptin, and caffeine are recommended for COVID-19 treatment after and clinical trial validation.Communicated by Ramaswamy H. Sarma.
Topics: Caffeine; Chymases; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33094705
DOI: 10.1080/07391102.2020.1835732 -
Molecules (Basel, Switzerland) Mar 2023Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main...
Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of -9.7, -9.6, and -9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.
Topics: Humans; COVID-19; SARS-CoV-2; Molecular Docking Simulation; Drug Repositioning; Sphingomyelin Phosphodiesterase; Protease Inhibitors; Molecular Dynamics Simulation; Antiviral Agents
PubMed: 37049752
DOI: 10.3390/molecules28072989 -
Molecules (Basel, Switzerland) Sep 2022Acanthamoeba species are capable of causing amoebic keratitis (AK). As a monotherapy, alpha-mangostin is effective for the treatment of AK; however, its bioavailability...
Acanthamoeba species are capable of causing amoebic keratitis (AK). As a monotherapy, alpha-mangostin is effective for the treatment of AK; however, its bioavailability is quite poor. Moreover, the efficacy of therapy is contingent on the parasite and virulent strains. To improve readiness against AK, it is necessary to find other derivatives with accurate target identification. Beta-tubulin (BT) has been used as a target for anti-Acanthamoeba (). In this work, therefore, a model of the BT protein of was constructed by homology modeling utilizing the amino acid sequence from NCBI (GenBank: JQ417907.1). Ramachandran Plot was responsible for validating the protein PDB. The verified BT PDB was used for docking with the specified ligand. Based on an improved docking score compared to alpha-mangostin (AM), two modified compounds were identified: 1,6-dihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C1) and 1,6-dihydroxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C2). In addition, molecular dynamics simulations were conducted to analyze the interaction characteristics of the two bound BT-new compound complexes. During simulations, the TRP9, ARG50, VAL52, and GLN122 residues of BT-C1 that align to the identical residues in BT-AM generate consistent hydrogen bond interactions with 0-3 and 0-2. However, the BT-C2 complex has a different binding site, TYR 258, ILE 281, and SER 302, and can form more hydrogen bonds in the range 0-4. Therefore, this study reveals that C1 and C2 inhibit BT as an additive or synergistic effect; however, further in vitro and in vivo studies are needed.
Topics: Acanthamoeba; Acanthamoeba Keratitis; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Tubulin; Xanthones
PubMed: 36234875
DOI: 10.3390/molecules27196338 -
Philosophical Transactions of the Royal... Jun 2018While the theory of protein folding is well developed, including concepts such as rugged energy landscape, folding funnel, etc., the same degree of understanding has not... (Review)
Review
While the theory of protein folding is well developed, including concepts such as rugged energy landscape, folding funnel, etc., the same degree of understanding has not been reached for the description of the dynamics of allosteric transitions in proteins. This is not only due to the small size of the structural change upon ligand binding to an allosteric site, but also due to challenges in designing experiments that directly observe such an allosteric transition. On the basis of recent pump-probe-type experiments (Buchli 2013 , 11 725-11 730. (doi:10.1073/pnas.1306323110)) and non-equilibrium molecular dynamics simulations (Buchenberg 2017 , E6804-E6811. (doi:10.1073/pnas.1707694114)) studying an photoswitchable PDZ2 domain as model for an allosteric transition, we outline in this perspective how such a description of allosteric communication might look. That is, calculating the dynamical content of both experiment and simulation (which agree remarkably well with each other), we find that allosteric communication shares some properties with downhill folding, except that it is an 'order-order' transition. Discussing the multiscale and hierarchical features of the dynamics, the validity of linear response theory as well as the meaning of 'allosteric pathways', we conclude that non-equilibrium experiments and simulations are a promising way to study dynamical aspects of allostery.This article is part of a discussion meeting issue 'Allostery and molecular machines'.
Topics: Allosteric Regulation; Models, Molecular; Molecular Dynamics Simulation; Protein Folding; Protein Interaction Maps; Proteins
PubMed: 29735740
DOI: 10.1098/rstb.2017.0187