Assessing the mechanism of fast‐cycling cancer‐associated mutations of Rac1 small Rho GTPase

Protein Science, Год журнала: 2024, Номер 33(4)

Опубликована: Март 19, 2024

Rho-GTPases proteins function as molecular switches alternating from an active to inactive state upon Guanosine triphosphate (GTP) binding and hydrolysis diphosphate (GDP). Among them, Rac subfamily regulates cell dynamics, being overexpressed in distinct cancer types. Notably, these are object of frequent cancer-associated mutations at Pro29 (P29S, P29L, P29Q). To assess the impact on Rac1 structure function, we performed extensive all-atom dynamics simulations wild-type (wt) oncogenic isoforms this protein GDP- GTP-bound states. Our results unprecedentedly elucidate that P29Q/S-induced structural dynamical perturbations core domain weaken catalytic site Mg

Язык: Английский

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Viral RNA Replication Suppression of SARS-CoV-2: Atomistic Insights into Inhibition Mechanisms of RdRp Machinery by ddhCTP

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(5), С. 1593 - 1604

Опубликована: Фев. 27, 2024

The nonstructural protein 12, known as RNA-dependent RNA polymerase (RdRp), is essential for both replication and repair of the viral genome. RdRp SARS-CoV-2 has been used a promising candidate drug development since inception COVID-19 spread. In this work, we performed an

Язык: Английский

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On the Role of Temperature in the Depolymerization of PET by FAST‐PETase: An Atomistic Point of View on Possible Active Site Pre‐Organization and Substrate‐Destabilization Effects

ChemBioChem, Год журнала: 2023, Номер 24(20)

Опубликована: Авг. 9, 2023

Enzyme FAST-PETase, recently obtained by a machine learning approach, can depolymerize poly(ethylene terephthalate) (PET), synthetic resin employed in plastics and clothing fibers. Therefore it represents promising solution for the recycling of PET-based materials. In this study, model PET was adopted to describe substrate, all-atoms classical molecular dynamics (MD) simulations on apo- substrate-bound FAST-PETase were carried out at 30 50 °C provide atomistic details binding step catalytic cycle. Comparative analysis shed light interactions occurring between 4PET °C, optimal working conditions enzyme. Pre-organization enzyme active sites has been highlighted, while MD FAST-PETase:4PET pointed occurrence solvent-inaccessible conformations substrate promoted Indeed, neither these observed during alone performed 30, 150 °C. The led us propose that, is pre-organized bind that site promote more reactive conformation thus enhancing activity

Язык: Английский

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On the dual role of (+)-catechin as primary antioxidant and inhibitor of viral proteases

Computers in Biology and Medicine, Год журнала: 2024, Номер 180, С. 108953 - 108953

Опубликована: Июль 31, 2024

Natural antioxidants have become the subject of many investigations due to role that they play in reduction oxidative stress. Their main scavenging mechanisms concern direct inactivation free radicals and coordination metal ions involved Fenton-like reactions. Recently, increasing attention has been paid non-covalent inhibition enzymes different diseases by antioxidants. Here, a computational investigation on primary antioxidant power (+)-catechin against

Язык: Английский

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Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(12), С. 9849 - 9849

Опубликована: Июнь 7, 2023

In this work, we elucidated some key aspects of the mechanism action cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare Thermus aquaticus (Taq) DNA polymerase three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP 5'-(2'-deoxy)-guanosine-triphosphate}, using canonical as a reference, presence DNA. The goal elucidate binding site between Taq tested nucleotide derivatives, providing valuable atomistic insights. Unbiased dynamics simulations (200 ns for each complex) explicit water molecules were performed on four ternary complexes, yielding significant findings that contribute better understanding experimental results. highlighted crucial role specific α-helix (O-helix) within fingers subdomain, which facilitates proper geometry functional contacts incoming template needed incorporation into polymerase. revealed complex 1 exhibits much lower affinity than complexes 2-3. affinities metabolites 2-3 found be quite similar those natural dGTP, resulting rate compared These could have implications action, high intracellular availability nucleobases might promote competitive platinated nucleotides over attachment study's insights active suggest may been previously underestimated.

Язык: Английский

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Trapping a non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase

Physical Chemistry Chemical Physics, Год журнала: 2023, Номер 26(3), С. 1792 - 1808

Опубликована: Дек. 11, 2023

The RNA dependent polymerase (RdRp) in SARS-CoV-2 is a highly conserved enzyme responsible for viral genome replication/transcription. To understand how the RdRp achieves fidelity control during such processes, here we computationally investigate natural non-cognate

Язык: Английский

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Flavone Derivatives as Potential Inhibitors of SARS-Cov-2rdrp through Computational Studies

Journal Of Biochemical Technology, Год журнала: 2023, Номер 14(4), С. 74 - 82

Опубликована: Янв. 1, 2023

The objective of this study is to identify potential targets within the SARS-CoV-2 RdRp for discovery novel inhibitors derived from therapeutic natural compounds sourced aromatic and medicinal plants. In course study, a library was generated containing five naturally occurring flavone derivatives (4a, 4b, 4c, 4d, 4e) in conjunction with standard favipiravir-RTP. underwent an in-silico methodology involving critical steps, including (a) evaluating ADM

Язык: Английский

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Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 4, 2023

Abstract The RNA dependent polymerase (RdRp) in SARS-CoV-2 is a highly conserved enzyme responsible for viral genome replication/transcription. Here we investigate computationally natural non-cognate vs cognate nucleotide addition cycle (NAC) and intrinsic selectivity during the RdRp elongation, focusing prechemically from initial substrate binding (enzyme active site open) to insertion (active closed) of contrast with one-step only process. Current studies have been first carried out using microsecond ensemble equilibrium all-atom molecular dynamics (MD) simulations. Due slow conformational changes (from open accompanying selection, enhanced or umbrella sampling methods further employed calculate free energy profiles NTP insertion. Our show notable stability noncognate dATP GTP upon active-site state. results indicate that while ATP Remdesivir drug analogue (RDV-TP) are biased be stabilized closed state, can well trapped off-path configurations. work thus presents an mechanism fidelity control replication.

Язык: Английский

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Molecular Dynamics and QM/MM to Understand Genome Organization and Reproduction in Emerging RNA Viruses

Elsevier eBooks, Год журнала: 2023, Номер unknown, С. 895 - 909

Опубликована: Апрель 27, 2023

Язык: Английский

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