Understanding the Hsp90 N-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922)

The spike protein of SARS-CoV-2 binds to ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analysis at molecular, amino acid (AA) and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex, including the MD simulations with molecular mechanics generalized Born surface area (MM-GBSA) method to predict binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q493, Y505, Q498, N501, T500, N487, Y449, F486, K417, Y489, F456, Y495, and L455 have been identified as hotspots in RBD, while those in ACE2 are K353, K31, D30, D355, H34, D38, Q24, T27, Y83, Y41, E35, and E37. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q493, N501, F486, K417, and F456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. The DFT results reveal that N487, Q493, Y449, T500, G496, G446 and G502 in RBD form pairs via specific hydrogen bonding with Q24, H34, E35, D38, Y41, Q42 and K353 in ACE2.

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A Cu(II)–ATP complex efficiently catalyses enantioselective Diels–Alder reactions

Nature Communications ◽

10.1038/s41467-020-18554-x ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Changhao Wang ◽

Qianqian Qi ◽

Wenying Li ◽

Jingshuang Dang ◽

Min Hao ◽

...

Keyword(s):

Metal Complexes ◽

Density Functional ◽

Bond Cleavage ◽

High Reactivity ◽

Diels Alder ◽

Functional Theory ◽

Catalytic Mechanisms ◽

Key Residues ◽

Chemical Selection ◽

Selection Of

Abstract Natural biomolecules have been used extensively as chiral scaffolds that bind/surround metal complexes to achieve stereoselectivity in catalytic reactions. ATP is ubiquitously found in nature as an energy-storing molecule and can complex diverse metal cations. However, in biotic reactions ATP-metal complexes are thought to function mostly as co-substrates undergoing phosphoanhydride bond cleavage reactions rather than participating in catalytic mechanisms. Here, we report that a specific Cu(II)-ATP complex (Cu2+·ATP) efficiently catalyses Diels-Alder reactions with high reactivity and enantioselectivity. We investigate the substrates and stereoselectivity of the reaction, characterise the catalyst by a range of physicochemical experiments and propose the reaction mechanism based on density functional theory (DFT) calculations. It is found that three key residues (N7, β-phosphate and γ-phosphate) in ATP are important for the efficient catalytic activity and stereocontrol via complexation of the Cu(II) ion. In addition to the potential technological uses, these findings could have general implications for the chemical selection of complex mixtures in prebiotic scenarios.

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Key Interacting Residues Between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamic Simulation and Density Functional Calculation

10.26434/chemrxiv.14582484 ◽

2021 ◽

Author(s):

Bahaa Jawad ◽

Puja Adhikari ◽

Rudolf Podgornik ◽

Wai-Yim Ching

Keyword(s):

Density Functional ◽

Vaccine Development ◽

Hydrophobic Interactions ◽

Binding Free Energy ◽

Tight Binding ◽

Md Simulations ◽

Functional Theory ◽

Generalized Born ◽

The Density Functional Theory ◽

Key Residues

The spike protein of SARS-CoV-2 binds to ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analysis at molecular, amino acid (AA) and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex, including the MD simulations with molecular mechanics generalized Born surface area (MM-GBSA) method to predict binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q493, Y505, Q498, N501, T500, N487, Y449, F486, K417, Y489, F456, Y495, and L455 have been identified as hotspots in RBD, while those in ACE2 are K353, K31, D30, D355, H34, D38, Q24, T27, Y83, Y41, E35, and E37. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q493, N501, F486, K417, and F456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. The DFT results reveal that N487, Q493, Y449, T500, G496, G446 and G502 in RBD form pairs via specific hydrogen bonding with Q24, H34, E35, D38, Y41, Q42 and K353 in ACE2.

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Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone

International Journal of Molecular Sciences ◽

10.3390/ijms22031373 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1373

Author(s):

Ryo Kishida ◽

Shosuke Ito ◽

Manickam Sugumaran ◽

Ryan Lacdao Arevalo ◽

Hiroshi Nakanishi ◽

...

Keyword(s):

Density Functional Theory ◽

Michael Addition ◽

Density Functional ◽

Activation Energies ◽

Atomic Scale ◽

Carbonyl Groups ◽

Binding Mechanism ◽

Bridge Site ◽

Functional Theory ◽

Sh Group

Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the –SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys–S−) to DQ. Interestingly, the C2–S bonded intermediate was less energetically stable than the C6–S bonded case. Furthermore, the most preferred Cys–S−-attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3–C4 bridge site) but not on the C5 site. This structure allows the Cys–S− to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5–S (and C2–S) intermediate into 5-S-cysteinyldopa (and 2-S-cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys–S− to DQ proceeds via the following path: (i) coordination of Cys–S− to C3–C4 bridge, (ii) migration of Cys–S− to C5 (C2), (iii) proton rearrangement from cysteinyl –NH3+ to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4).

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Elucidating the structures and cooperative binding mechanism of cesium salts to the multitopic ion-pair receptor through density functional theory calculations

Dalton Transactions ◽

10.1039/c5dt01095k ◽

2015 ◽

Vol 44 (35) ◽

pp. 15450-15462 ◽

Cited By ~ 10

Author(s):

Biswajit Sadhu ◽

Mahesh Sundararajan ◽

Gunasekaran Velmurugan ◽

Ponnambalam Venuvanalingam

Keyword(s):

Quantum Chemical ◽

Density Functional ◽

Density Functional Theory Calculations ◽

Ion Pair ◽

Cooperative Binding ◽

Binding Mechanism ◽

Functional Theory ◽

Chemical Studies ◽

Quantum Chemical Studies ◽

Cesium Salts

Quantum chemical studies predict the binding of Cesium salts to multitopic ion-pair receptor is through cooperative mechanism.

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The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2

10.21203/rs.3.rs-160254/v1 ◽

2021 ◽

Author(s):

Joyanta Kumar Saha ◽

Md. Jahir Raihan

Keyword(s):

Density Functional ◽

Binding Energies ◽

Spike Protein ◽

Binding Mechanism ◽

Functional Theory ◽

Modeling Techniques ◽

Charge Analysis ◽

The Stability ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding affinity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are − 17.8 kcal/mol and − 20.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study confirms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.

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Doping effects on the geometric and electronic structure of tin clusters

Physical Chemistry Chemical Physics ◽

10.1039/c9cp05124d ◽

2019 ◽

Vol 21 (44) ◽

pp. 24478-24488 ◽

Cited By ~ 1

Author(s):

Martin Gleditzsch ◽

Marc Jäger ◽

Lukáš F. Pašteka ◽

Armin Shayeghi ◽

Rolf Schäfer

Keyword(s):

Density Functional Theory ◽

Electronic Structure ◽

Density Functional ◽

Beam Deflection ◽

Functional Theory ◽

Doping Effects ◽

Depth Analysis ◽

Trajectory Simulations

In depth analysis of doping effects on the geometric and electronic structure of tin clusters via electric beam deflection, numerical trajectory simulations and density functional theory.

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