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| 2. |
- Guanglin, Kuang, 1987-, et al.
(författare)
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Mechanistic Insight into the Binding Profile of DCVJ and alpha-Synuclein Fibril Revealed by Multiscale Simulations
- 2019
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Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 10:1, s. 610-617
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is a serious neuro-degenerative disease and is characterized by abnormal alpha-synuclein (alpha-syn) accumulation in Lewy bodies (LB) and 2 Lewy neurites (LN), which makes alpha-syn an important imaging target for PD. An imaging probe that quantifies fibrillar alpha-syn can enhance the clinical diagnosis of PD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the alpha-syn fibril in the brain. In this paper, we study the binding profile of fibrillar alpha-syn with a fluorescent probe 4-(dicyanovinyl)julolidine (DCVJ), which is being explored for identifying alpha-syn imaging agents. A multiscale simulation workflow including molecular docking, molecular dynamics, metadynamics, and QM/MM calculations was implemented. We find that DCVJ can bind to multiple sites of alpha-syn which are located either at the surface or in the core. Free energy calculations using implicit solvent models reveal that the most favorable binding mode for DCVJ is associated with the core binding site and is further confirmed by metadyamics simulation. Besides, a dynamic binding pathway is discovered, which reveals that DCVJ binds gradually into the core of the fibril passing through several intermediate states. The conformational arrest of the dicyano vinyl group in the fibrillar environment could explain the reason behind the fibril-specific fluorescence of DCVJ. Furthermore, based on hybrid QM/MM calculations, the molecular geometry of the dicyano vinyl group is found to be environment specific which explains why DCVJ serves as a staining agent for such fibrillar-like environments. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of alpha-syn and explain their fibrillar-specific optical properties, a knowledge that in turn can be used to guide the design and development of compounds with higher affinity and selectivity for alpha-syn using structure-based strategies.
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| 3. |
- Guanglin, Kuang, 1987-
(författare)
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Theoretical Studies of Protein-Ligand Interactions
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The protein-ligand interaction is an important issue in rational drug design and protein function research. This thesis focuses on the study of protein-ligand interactions using various molecular modeling methods, which are used in combination to predict the binding modes and calculate the binding free energies of several important protein-ligand systems, as summarized below.In Paper I, we investigated the binding profile of a type I positive allosteric modulator (PAM) NS-1738 with the α7-nicotinic acetylcholine receptor (α7-nAChR). NS-1738 is found to have three different binding sites on α7-nAChR and has moderate binding affinities to the receptor.In Paper II, we revealed the binding mechanism of a PET radio-ligand [18F]ASEM with α7-nAChR. Using metadynamics simulations, we managed to find a stable state which is not observed in molecular docking and unbiased molecular dynamics simulations. Free energy analysis further confirmed that this stable state is the global minimum with respect to the selected collective variables.In Paper III, we studied the binding modes and binding affinities of two probes (AZD2184 and thioflavin T) for the detection of amyloid β(1-42) fibrils in clinical studies. We found that AZD2184 and thioflavin T are able to bind to several sites of the Aβ(1-42) fibril. Due to the small size, planarity and neutrality of AZD2184, it binds more strongly with Aβ(1-42) fibril at all sites. By contrast, thioflavin T has more significant conformational changes after binding, which is the reason that thioflavin T can be used as a fluorescent probe in in vitro studies.In Paper IV, we studied the binding profile of PtdIns(3,4,5)P3 with the plecsktrin homology (PH) domain of Saprolegnia monoica cellulose synthase. We first studied the binding modes of the inositol groups with the PH domain in solution, the results of which were then used to guide the modeling of the binding mode of PtdIns(3,4,5)P3 in a membrane with the PH domain.
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| 6. |
- Zhou, Yang, 1986-, et al.
(författare)
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Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes
- 2019
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 59:9, s. 3910-3918
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Tidskriftsartikel (refereegranskat)abstract
- Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[F-18]fluorodibenzo[b,d]thiophen e 5,5-dioxide ([F-18]ASEM) from a chimera structure of the alpha 7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.
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| 7. |
- Zhou, Yang, et al.
(författare)
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In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification
- 2021
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Ingår i: RSC Advances. - : ROYAL SOC CHEMISTRY. - 2046-2069. ; 11:7, s. 3942-3951
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Tidskriftsartikel (refereegranskat)abstract
- The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is implicated in a variety of neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. The progress of these disorders can be studied using positron emission tomography (PET) with radiotracers for alpha 7-nAChR. [F-18]ASEM and [F-18] para-ASEM (also referred to as [F-18]DBT-10) are novel and potent alpha 7-nAChR PET radiotracers which have successfully been used in human subjects and nonhuman primates, though further improvement of them is still a pressing task in the community of neurodegeneration research. In this work, we demonstrate the use of modern in silico techniques to predict the binding modes, binding strengths, and residence times for molecular PET tracers binding to proteins, using ASEM and DBT-10 as a showcase of the predictive and interpretational power of such techniques, in particular free energy perturbation theory. The corresponding compounds were synthesized and further tested by in vitro binding experiment for validation. Encouragingly, our in silico modeling can correctly predict the binding affinities of the ASEM analogues. The structure-activity relationships for the ortho- and para-substitutions are well explained at the atomistic level and provide structure-based guiding for the future development of PET tracers for alpha 7-nAChR. A discussion is presented on the complementary use of in silico rational methods based on atomic and electronic principles for in vitro characterization of PET tracers.
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| 8. |
- Zhou, Yang, 1986-, et al.
(författare)
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Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection
- 2018
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 20:36, s. 23222-23232
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Tidskriftsartikel (refereegranskat)abstract
- ATAD2 has emerged as a promising bromodomain (BRD)-containing therapeutic drug target in multiple human cancers. However, recent druggability assessment studies predicted ATAD2's BRD as a target 'difficult to drug' because its binding pocket possesses structural features that are unfeasible for ligand binding. Here, by using all-atom molecular dynamics simulations and an advanced metadynamics method, we demonstrate a dynamic view of the binding pocket features which can hardly be obtained from the "static" crystal data. The most important features disclosed from our simulation data, include: (1) a distinct 'open-to-closed' conformational switch of the ZA loop region in the context of peptide or ligand binding, akin to the induced fit mechanism of molecular recognition, (2) a dynamic equilibrium of the BC loop "in" and "out" conformations, highlighting a role in the conformational selection mechanism for ligand binding, and (3) a new binding region identified distal to the histone-binding pocket that might have implications in bromodomain biology and in inhibitor development. Moreover, based on our simulation results, we propose a model for an "auto-regulatory" mechanism of ATAD2's BRD for histone binding. Overall, the results of this study will not only have implications in bromodomain biology but also provide a theoretical basis for the discovery of new ATAD2's BRD inhibitors.
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| 9. |
- Zou, Rongfeng, et al.
(författare)
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Free Energy Profile and Kinetics for Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Motivated by that inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for drug design and that understanding of this process poses a most significant challenging task, we present an atomistic level simulation of the coupled folding and binding process linking the IDP p53 to MDM2. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD) we estimate the binding free energy, the unbinding rate and the binding rate. By analyzing the stable intermediates, we uncover the role of nonnative interactions played in the p53-MDM2 binding/unbinding process. We use a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced fit mechanism which proceeds in a stepwise fashion. In general, InMetaD gave consistent results with BE-MetaD in terms of binding mechanism and intermediates, proving the robustness of our studies of the p53-MDM2 system using metadynamics. The results contribute to the in-depth understanding for the coupled folding and binding process that is needed for the design of MDM2 inhibitors.
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| 10. |
- Zou, Rongfeng, et al.
(författare)
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Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
- 2020
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 60:3, s. 1551-1558
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Tidskriftsartikel (refereegranskat)abstract
- Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Because inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD), we estimated the binding free energy, the unbinding rate, and the binding rate. By analyzing the stable intermediates, we uncovered the role non-native interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced-fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for gaining an in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.
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