Exploring the interaction mechanism between potential inhibitor and multi-target Mur enzymes of mycobacterium tuberculosis using molecular docking, molecular dynamics simulation, principal component analysis, free energy landscape, dynamic cross-correlation matrices, vector movements, and binding free energy calculation

Kumari, Madhuri; Singh, Ruhar; Subbarao, Naidu

doi:10.1080/07391102.2021.1989040

Cited by 32 publications

(11 citation statements)

References 46 publications

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“…A more uniform and coherent correlation in M1, but an incoherent and localized correlation in M2, was observed by the dynamic cross-correlation map (DCCM) and dynamic cross-correlation network (DCCN) analyses [ 71 , 72 , 73 , 74 ] ( Figure 2 G,J,K). The differences observed in M2 were also identified in M3 and M4; although the overall correlation was not as pronounced as in M1 ( Figure 2 H,I,L,M).…”

Section: Resultsmentioning

confidence: 93%

Archaeal Lipids Regulating the Trimeric Structure Dynamics of Bacteriorhodopsin for Efficient Proton Release and Uptake

Chen

Ding

Sun

et al. 2022

IJMS

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S-TGA-1 and PGP-Me are native archaeal lipids associated with the bacteriorhodopsin (bR) trimer and contribute to protein stabilization and native dynamics for proton transfer. However, little is known about the underlying molecular mechanism of how these lipids regulate bR trimerization and efficient photocycling. Here, we explored the specific binding of S-TGA-1 and PGP-Me with the bR trimer and elucidated how specific interactions modulate the bR trimeric structure and proton release and uptake using long-term atomistic molecular dynamic simulations. Our results showed that S-TGA-1 and PGP-Me are essential for stabilizing the bR trimer and maintaining the coherent conformational dynamics necessary for proton transfer. The specific binding of S-TGA-1 with W80 and K129 regulates proton release on the extracellular surface by forming a “Glu-shared” model. The interaction of PGP-Me with K40 ensures proton uptake by accommodating the conformation of the helices to recruit enough water molecules on the cytoplasmic side. The present study results could fill in the theoretical gaps of studies on the functional role of archaeal lipids and could provide a reference for other membrane proteins containing similar archaeal lipids.

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Section: Resultsmentioning

confidence: 93%

Archaeal Lipids Regulating the Trimeric Structure Dynamics of Bacteriorhodopsin for Efficient Proton Release and Uptake

Chen

Ding

Sun

et al. 2022

IJMS

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“…The DCCM algorithm was applied to gather insights into the correlated motions of the lead compounds through molecular dynamics simulations. This was accomplished by calculating the cross-correlations of Cα atoms using the R programming language’s Bio3D package [ 51 ]. In this research, all post-molecular dynamics simulation results were obtained using AMBER v2022 software.…”

Section: Resultsmentioning

confidence: 99%

In Silico Identification of Lead Compounds for Pseudomonas Aeruginosa PqsA Enzyme: Computational Study to Block Biofilm Formation

et al. 2023

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Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium implicated in acute and chronic nosocomial infections and a leading cause of patient mortality. Pseudomonas aeruginosa infections are frequently associated with the development of biofilms, which give the bacteria additional drug resistance and increase their virulence. The goal of this study was to find strong compounds that block the Anthranilate-CoA ligase enzyme made by the pqsA gene. This would stop the P. aeruginosa quorum signaling system. This enzyme plays a crucial role in the pathogenicity of P. aeruginosa by producing autoinducers for cell-to-cell communication that lead to the production of biofilms. Pharmacophore-based virtual screening was carried out utilizing a library of commercially accessible enzyme inhibitors. The most promising hits obtained during virtual screening were put through molecular docking with the help of MOE. The virtual screening yielded 7/160 and 10/249 hits (ZINC and Chembridge). Finally, 2/7 ZINC hits and 2/10 ChemBridge hits were selected as potent lead compounds employing diverse scaffolds due to their high pqsA enzyme binding affinity. The results of the pharmacophore-based virtual screening were subsequently verified using a molecular dynamic simulation-based study (MDS). Using MDS and post-MDS, the stability of the complexes was evaluated. The most promising lead compounds exhibited a high binding affinity towards protein-binding pocket and interacted with the catalytic dyad. At least one of the scaffolds selected will possibly prove useful for future research. However, further scientific confirmation in the form of preclinical and clinical research is required before implementation.

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“…Dynamic cross-correlation map (DCCM) Cij was introduced to judge the time-dependent motion of all Cα atom pairs [ 52 ], which has been extensively used to study protein dynamics [ 53 , 54 , 55 ]. The formula is as follows:

where L represents the number of frames; ΔR i represents the change of spatial position of a certain residue or atom in two frames before and after; C ij represents the correlation between the changes of a group of residues or atom vectors, with values ranging from −1 to 1.…”

Section: Methodsmentioning

confidence: 99%

“…Dynamic cross-correlation map (DCCM) Cij was introduced to judge the time-dependent motion of all Cα atom pairs [52], which has been extensively used to study protein dynamics [53][54][55]. The formula is as follows:…”

Section: Dynamic Cross-correlation Mapmentioning

confidence: 99%

The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs

Zhao

Zhang

et al. 2023

Biomolecules

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The aggregation of alpha-synuclein (α-Syn) is closely related to the occurrence of some neurodegenerative diseases such as Parkinson’s disease. The misfolding of α-Syn monomer plays a key role in the formation of aggregates and extension of fibril. However, the misfolding mechanism of α-Syn remains elusive. Here, three different α-Syn fibrils (isolated from a diseased human brain, generated by in vitro cofactor-tau induction, and obtained by in vitro cofactor-free induction) were selected for the study. The misfolding mechanisms of α-Syn were uncovered by studying the dissociation of the boundary chains based on the conventional molecular dynamics (MD) and Steered MD simulations. The results showed that the dissociation paths of the boundary chains in the three systems were different. According to the reverse process of dissociation, we concluded that in the human brain system, the binding of the monomer and template starts from the C-terminal and gradually misfolds toward the N-terminal. In the cofactor-tau system, the monomer binding starts from residues 58–66 (contain β3), followed by the C-terminal coil (residues 67–79). Then, the N-terminal coil (residues 36–41) and residues 50–57 (contain β2) bind to the template, followed by residues 42–49 (contain β1). In the cofactor-free system, two misfolding paths were found. One is that the monomer binds to the N/C-terminal (β1/β6) and then binds to the remaining residues. The other one is that the monomer binds sequentially from the C- to N-terminal, similar to the human brain system. Furthermore, in the human brain and cofactor-tau systems, electrostatic interactions (especially from residues 58–66) are the main driving force during the misfolding process, whereas in the cofactor-free system, the contributions of electrostatic and van der Waals interactions are comparable. These results may provide a deeper understanding for the misfolding and aggregation mechanism of α-Syn.

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Cited by 32 publications

References 46 publications

Archaeal Lipids Regulating the Trimeric Structure Dynamics of Bacteriorhodopsin for Efficient Proton Release and Uptake

Archaeal Lipids Regulating the Trimeric Structure Dynamics of Bacteriorhodopsin for Efficient Proton Release and Uptake

In Silico Identification of Lead Compounds for Pseudomonas Aeruginosa PqsA Enzyme: Computational Study to Block Biofilm Formation

The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs

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