scholarly journals Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4085 ◽  
Author(s):  
Ashwini Machhindra Londhe ◽  
Changdev Gorakshnath Gadhe ◽  
Sang Min Lim ◽  
Ae Nim Pae
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Binding Pocket ◽  
Umbrella Sampling ◽  
Valuable Insight ◽  
Protein Protein Interaction ◽  
Kelch Domain ◽  
Insight Into

In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several neurodegenerative diseases like cancer, diabetes, and cardiomyopathy. A better understanding of the five sub-pocket binding sites for Nrf2 (ETGE and DLG motifs) inside the Kelch domain would expedite the inhibitor design process. We selected four protein–ligand complexes with distinct co-crystal ligands and binding occupancies inside the Nrf2 binding site. We performed 100 ns of MD simulation for each complex and analyzed the trajectories. From the results, it is evident that one ligand (1VV) has flipped inside the binding pocket, whereas the remaining three were stable. We found that Coulombic (Arg483, Arg415, Ser363, Ser508, and Ser602) and Lennard–Jones (Tyr525, Tyr334, and Tyr572) interactions played a significant role in complex stability. The obtained binding free energy values from US simulations were consistent with the potencies of simulated ligands. US simulation highlight the importance of basic and aromatic residues in the binding pocket. A detailed description of the dissociation process brings valuable insight into the interaction of the four selected protein–ligand complexes, which could help in the future to design more potent PPI inhibitors.

scholarly journals Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

2019 ◽  
Vol 20 (18) ◽  
pp. 4468 ◽  
Author(s):  
Kiani ◽  
Ranaghan ◽  
Jabeen ◽  
Mulholland
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Binding Pocket ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Metabolic Enzyme ◽  
New Chemical Entities ◽  
Cyp3a4 Inhibitors ◽  
Cytochrome P450 Family

The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects.

scholarly journals KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability

2021 ◽  
Vol 22 (10) ◽  
pp. 5408
Author(s):  
Carter Wilson ◽  
Megan Chang ◽  
Mikko Karttunen ◽  
Wing-Yiu Choy
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Md Simulations ◽  
Covalent Modification ◽  
Additional Insight ◽  
New Class ◽  
Kelch Domain ◽  
Cancer Mutations ◽  
Mutagenic Effects ◽  
Insight Into

We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant’s mode of action.

scholarly journals Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5696
Author(s):  
Wei Lim Chong ◽  
Koollawat Chupradit ◽  
Sek Peng Chin ◽  
Mai Mai Khoo ◽  
Sook Mei Khor ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Protein Binding ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Single Point ◽  
Md Simulations ◽  
Nanoparticle Tracking Analysis ◽  
Buffer Solution ◽  
Dynamics Simulations

Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

scholarly journals Exploring the Binding Interaction of Raf Kinase Inhibitory Protein With the N-Terminal of C-Raf Through Molecular Docking and Molecular Dynamics Simulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Shraddha Parate ◽  
Shailima Rampogu ◽  
Gihwan Lee ◽  
Jong Chan Hong ◽  
Keun Woo Lee
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Sites ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Web Servers ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein

Protein-protein interactions are indispensable physiological processes regulating several biological functions. Despite the availability of structural information on protein-protein complexes, deciphering their complex topology remains an outstanding challenge. Raf kinase inhibitory protein (RKIP) has gained substantial attention as a favorable molecular target for numerous pathologies including cancer and Alzheimer’s disease. RKIP interferes with the RAF/MEK/ERK signaling cascade by endogenously binding with C-Raf (Raf-1 kinase) and preventing its activation. In the current investigation, the binding of RKIP with C-Raf was explored by knowledge-based protein-protein docking web-servers including HADDOCK and ZDOCK and a consensus binding mode of C-Raf/RKIP structural complex was obtained. Molecular dynamics (MD) simulations were further performed in an explicit solvent to sample the conformations for when RKIP binds to C-Raf. Some of the conserved interface residues were mutated to alanine, phenylalanine and leucine and the impact of mutations was estimated by additional MD simulations and MM/PBSA analysis for the wild-type (WT) and constructed mutant complexes. Substantial decrease in binding free energy was observed for the mutant complexes as compared to the binding free energy of WT C-Raf/RKIP structural complex. Furthermore, a considerable increase in average backbone root mean square deviation and fluctuation was perceived for the mutant complexes. Moreover, per-residue energy contribution analysis of the equilibrated simulation trajectory by HawkDock and ANCHOR web-servers was conducted to characterize the key residues for the complex formation. One residue each from C-Raf (Arg398) and RKIP (Lys80) were identified as the druggable “hot spots” constituting the core of the binding interface and corroborated by additional long-time scale (300 ns) MD simulation of Arg398Ala mutant complex. A notable conformational change in Arg398Ala mutant occurred near the mutation site as compared to the equilibrated C-Raf/RKIP native state conformation and an essential hydrogen bonding interaction was lost. The thirteen binding sites assimilated from the overall analysis were mapped onto the complex as surface and divided into active and allosteric binding sites, depending on their location at the interface. The acquired information on the predicted 3D structural complex and the detected sites aid as promising targets in designing novel inhibitors to block the C-Raf/RKIP interaction.

scholarly journals Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques

2020 ◽  
Author(s):  
Sebastian Wingbermühle ◽  
Lars V. Schäfer
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Replica Exchange ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Ligand Complex ◽  
Mhc I ◽  
Partial Dissociation

Enhanced sampling techniques are a promising approach to obtain reliable binding free energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of Umbrella Sampling (US), Replica Exchange with Solute Tempering 2 (REST2), Bias Exchange Umbrella Sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered Metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can handle best the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free energy minimum in the pMHC I under study. These findings might be relevant also for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.<br>

scholarly journals Fast and Flexible GPU Accelerated Binding Free Energy Calculations within the AMBER Molecular Dynamics Package

2018 ◽  
Author(s):  
Daniel J. Mermelstein ◽  
Lin Charles ◽  
Nelson Gard ◽  
Kretsch Rachael ◽  
J. Andrew McCammon ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Graphics Processing Units ◽  
Early Stage ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Design And Optimization ◽  
Time Required

AbstractAlchemical free energy calculations (AFE) based on molecular dynamics (MD) simulations are key tools in both improving our understanding of a wide variety of biological processes and accelerating the design and optimization of therapeutics for numerous diseases. Computing power and theory have, however, long been insufficient to enable AFE calculations to be routinely applied in early stage drug discovery. One of the major difficulties in performing AFE calculations is the length of time required for calculations to converge to an ensemble average. CPU implementations of MD based free energy algorithms can effectively only reach tens of nanoseconds per day for systems on the order of 50,000 atoms, even running on massively parallel supercomputers. Therefore, converged free energy calculations on large numbers of potential lead compounds are often untenable, preventing researchers from gaining crucial insight into molecular recognition, potential druggability, and other crucial areas of interest. Graphics Processing Units (GPUs) can help address this. We present here a seamless GPU implementation, within the PMEMD module of the AMBER molecular dynamics package, of thermodynamic integration (TI) capable of reaching speeds of >140 ns/day for a 44,907-atom system, with accuracy equivalent to the existing CPU implementation in AMBER. The implementation described here is currently part of the AMBER 18 beta code and will be an integral part of the upcoming version 18 release of AMBER.

Insight into the adsorption profiles of the Saprolegnia monoica chitin synthase MIT domain on POPA and POPC membranes by molecular dynamics simulation studies

2016 ◽  
Vol 18 (7) ◽  
pp. 5281-5290 ◽  
Author(s):  
Guanglin Kuang ◽  
Lijun Liang ◽  
Christian Brown ◽  
Qi Wang ◽  
Vincent Bulone ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Chitin Synthase ◽  
Dynamics Simulation ◽  
Simulation Methods ◽  
Simulation Studies ◽  
Insight Into

The binding mode and binding free energy of the Saprolegnia monoica chitin synthase MIT domain with the POPA membrane have been studied by molecular simulation methods.

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