scholarly journals Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations

2019 ◽  
Vol 20 (5) ◽  
pp. 1188 ◽  
Author(s):  
Ye Liu ◽  
Youzhong Wan ◽  
Jingxuan Zhu ◽  
Muxin Li ◽  
Zhengfei Yu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Catalytic Reaction ◽  
Pyridoxal Phosphate ◽  
Binding Free Energy ◽  
Enantiomeric Excess ◽  
Optical Purity ◽  
Aromatic Amino Acids ◽  
Lysosomal Storage Diseases ◽  
Md Simulations ◽  
Lysosomal Storage

The aminotransferase from Bacillus circulans (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.

scholarly journals Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 904 ◽  
Author(s):  
Arnold Amusengeri ◽  
Rolland Bantar Tata ◽  
Özlem Tastan Bishop
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Network Analysis ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Point Mutations ◽  
Md Simulations ◽  
Conformational Plasticity ◽  
New Perspective ◽  
The Impact

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

scholarly journals Enhancing Virtual Screening Efficiency in the Discovery of Human TMPRSS2 Inhibitor for Combating COVID-19

2021 ◽  
Author(s):  
Said A. H. Vuai ◽  
Marcelina M. Ogedjo ◽  
Isaac Onoka ◽  
Mtabazi G. Sahini ◽  
Daniel M Shadrack
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Catalytic Reaction ◽  
Binding Free Energy ◽  
Initial Point ◽  
Catalytic Triad ◽  
Dynamics Simulation ◽  
Hydrogen Bond Interaction ◽  
Screening Experiments

Abstract As the coronavirus disease 19 (COVID-19) pandemic continues to pose a health and economic crisis worldwide, the quest for drugs and/or vaccines against the virus continues. The human transmembrase protease serines 2 (TMPRSS2) has attracted attention as a target for drug discovery, as inhibition of its catalytic reaction would results in the inactivation of the proteolytic cleavage of the SARS-CoV-2 S protein. As a result, the inactivation prevents viral cell entry to the host’s cell. In this work, we screened and identified two potent molecules that interact and inhibit the catalytic reaction by using computational approaches. Two docking screening experiments were performed utilizing the crystal structure and holo ensemble structure obtained from molecular dynamics in bound form. There is enhancement and sensitivity of docking results to the holo ensemble as compared to the crystal structure. Compound 1 binds more stable than nafamostat by interacting with catalytic triad residue His296 and Ser441, thereby disrupting the already establish hydrogen bond interaction. The stability of the ligand-TMPRSS2 complexes was studied by molecular dynamics simulation, and the binding energy was re-scored by using MM-PBSA binding free energy. The obtained compounds may serve as initial point towards the discovery of potent TMPRSS2 inhibitors upon further in vivo validation.

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 Digalloyl Glycoside: A Potential Inhibitor of Trypanosomal PFK from Euphorbia abyssinica J.F. Gmel

Plants ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 173
Author(s):  
Seham S. El-Hawary ◽  
Rabab Mohammed ◽  
Nadia M. Lithy ◽  
Sameh Fekry AbouZid ◽  
Mostafa A. Mansour ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Tsetse Fly ◽  
In Vivo Studies ◽  
Spectroscopic Techniques ◽  
Phytochemical Investigation ◽  
High Level

Human African trypanosomiasis is an endemic infectious disease caused by Trypanosoma brucei via the bite of tsetse-fly. Most of the drugs used for the treatment, e.g., Suramin, have shown several problems, including the high level of toxicity. Accordingly, the discovery of anti-trypanosomal drugs from natural sources has become an urgent requirement. In our previous study on the anti-trypanosomal potential of Euphorbia species, Euphorbia abyssinica displayed significant anti-trypanosomal activity. Therefore, a phytochemical investigation of the methanolic extract of E. abyssinica was carried out. Twelve compounds, including two triterpenes (1, 2); one sterol-glucoside (4); three ellagic acid derivatives (3, 9, 11); three gallic acid derivatives (5, 6, 10); and three flavonoids (7, 8, 12), were isolated. The structures of isolated compounds were determined through different spectroscopic techniques. Compound (10) was obtained for the first time from genus Euphorbia while all other compounds except compound (4), were firstly reported in E. abyssinica. Consequently, an in silico study was used to estimate the anti-trypanosomal activity of the isolated compounds. Several compounds displayed interesting activity where 1,6-di-O-galloyl-d-glucose (10) appeared as the most potent inhibitor of trypanosomal phosphofructokinase (PFK). Moreover, molecular dynamics (MD) simulations and ADMET calculations were performed for 1,6-di-O-galloyl-d-glucose. In conclusion, 1,6-di-O-galloyl-d-glucose revealed high binding free energy as well as desirable molecular dynamics and pharmacokinetic properties; therefore, it could be suggested for further in vitro and in vivo studies for trypanosomiasis.

scholarly journals Mutagenesis of DsbAss is Crucial for the Signal Recognition Particle Mechanism in Escherichia coli: Insights from Molecular Dynamics Simulations

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 133 ◽  
Author(s):  
Faiza Durrani ◽  
Roquyya Gul ◽  
Muhammad Mirza ◽  
Naheed Kaderbhai ◽  
Matheus Froeyen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Molecular Dynamics ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Signal Sequence ◽  
Binding Free Energy ◽  
Signal Recognition Particle ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Dynamics Simulations

The disulfide bond signal sequence (DsbAss) protein is characterized as an important virulence factor in gram-negative bacteria. This study aimed to analyze the “alanine” alteration in the hydrophobic (H) region of DsbAss and to understand the conformational DsbAss alteration(s) inside the fifty-four homolog (Ffh)-binding groove which were revealed to be crucial for translocation of ovine growth hormone (OGH) to the periplasmic space in Escherichia coli via the secretory (Sec) pathway. An experimental design was used to explore the hydrophobicity and alteration of alanine (Ala) to isoleucine (Ile) in the tripartite structure of DsbAss. As a result, two DsbAss mutants (Ala at positions -11 and -13) with same hydrophobicity of 1.539 led to the conflicting translocation of the active OGH gene. We performed molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) binding free energy calculations to examine the interaction energetic and dynamic aspects of DsbAss/signal repetition particle 54 (SRP54) binding, which has a principle role in Escherichia coli Sec pathways. Although both DsbAss mutants retained helicity, the MD simulation analysis evidenced that altering Ala-13 changed the orientation of the signal peptide in the Ffh M binding domain groove, favored more stable interaction energies (MM-GBSA ΔGtotal = −140.62 kcal mol−1), and hampered the process of OGH translocation, while Ala-11 pointed outward due to unstable conformation and less binding energy (ΔGtotal = −124.24 kcal mol−1). Here we report the dynamic behavior of change of “alanine” in the H-domain of DsbAss which affects the process of translocation of OGH, where MD simulation and MM-GBSA can be useful initial tools to investigate the virulence of bacteria.

scholarly journals 3D-QSAR, Molecular Docking, and MD Simulations of Anthraquinone Derivatives as PGAM1 Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuwei Wang ◽  
Yifan Guo ◽  
Shaojia Qiang ◽  
Ruyi Jin ◽  
Zhi Li ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Rational Design ◽  
Binding Free Energy ◽  
3D Qsar ◽  
Md Simulations ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Wide Range ◽  
Anthraquinone Derivatives

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure–activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure–activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.

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.

scholarly journals S494 O-glycosylation site on the SARS-CoV-2 RBD affects the virus affinity to ACE2 and its infectivity; a molecular dynamics study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shadi Rahnama ◽  
Maryam Azimzadeh Irani ◽  
Mehriar Amininasab ◽  
Mohammad Reza Ejtehadi
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Glycosylation Site ◽  
Virus Infectivity ◽  
S Protein ◽  
Host Interaction ◽  
Binding Interface ◽  
Direct Binding

AbstractSARS-CoV-2 is a strain of Coronavirus family that caused the ongoing pandemic of COVID-19. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. By exploring the dynamics of three O-glycosylated models and the control systems of unglcosylated S4944 and S494D complexes, it was shown that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2. Calculation of the distances between RBD and two major H1, H2 helices of ACE2 and the interacting pairs of amino acids in the interface showed that the elongated O-glycan maintains these interactions by forming several polar contacts with the neighbouring residues while it would not interfere in the direct binding interface. Relative binding free energy of RBD-ACE2 is also more favorable in the O-glycosylated models with longer glycans. The increase of RBD binding affinity to ACE2 depends on the size of attached O-glycan. By increasing the size of O-glycan, the RBD-ACE2 binding affinity will increase. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.

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