Flavin oxidation state impacts on nitrofuran antibiotic binding orientation in nitroreductases

Nitroreductases catalyse the NAD(P)H-dependent nitro reduction in nitrofuran antibiotics, which activates them into cytotoxic molecules leading to cell death. The design of new effective nitrofuran antibiotics relies on knowledge of the kinetic mechanism and nitrofuran binding mode of microbial nitroreductases NfsA and NfsB. This has been hampered by multiple co-crystallisation studies revealing ligand binding in non-electron transfer competent states. In a recent study by Day et al. (2021) the authors investigated the likely reaction mechanism and mode of nitrofurantoin binding to NfsA using potentiometry, global kinetics analysis, crystallography and molecular dynamics simulations. Their findings suggest nitrofurantoin reduction proceeds via a direct hydride transfer from reduced FMN, while the crystallographic binding orientation is an inhibitory complex. Molecular dynamics simulations suggest ligand binding orientations is dependent on the oxidation state of the FMN. This study highlights the importance of utilising computational studies alongside traditional crystallographic approaches, when multiple stable ligand binding orientations can occur.

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Prediction of ligand binding mode among multiple cross-docking poses by molecular dynamics simulations

Journal of Computer-Aided Molecular Design ◽

10.1007/s10822-020-00340-y ◽

2020 ◽

Vol 34 (11) ◽

pp. 1195-1205

Author(s):

Kai Liu ◽

Hironori Kokubo

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Molecular Dynamics Simulations ◽

Binding Mode ◽

Cross Docking ◽

Multiple Cross ◽

Dynamics Simulations

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A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: Probing the binding pathway of dasatinib to Src-kinase

10.1101/650440 ◽

2019 ◽

Cited By ~ 1

Author(s):

Farzin Sohraby ◽

Mostafa Javaheri Moghadam ◽

Masoud Aliyar ◽

Hassan Aryapour

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Molecular Dynamics Simulations ◽

Src Kinase ◽

Deep Understanding ◽

Binding Mode ◽

Dynamics Simulation ◽

Dynamics Simulations ◽

Computational Resources ◽

Binding Mechanisms

AbstractSmall molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased molecular dynamics simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased molecular dynamics simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) molecular dynamics simulations, in this case a protein-ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nano-second timescales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction.

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The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽

10.3390/molecules26051250 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1250

Author(s):

Hien T. T. Lai ◽

Alejandro Giorgetti ◽

Giulia Rossetti ◽

Toan T. Nguyen ◽

Paolo Carloni ◽

...

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Molecular Dynamics Simulations ◽

Binding Site ◽

Transmembrane Protein ◽

Free Form ◽

Experimental Investigations ◽

Terminal Part ◽

Dynamics Simulations ◽

Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

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