In the footsteps of an inhibitor unbinding from the active site of human carbonic anhydrase II

Khatua, Satyajit; Taraphder, Srabani

doi:10.1080/07391102.2022.2048075

Cited by 3 publications

(4 citation statements)

References 80 publications

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“…It is well accepted that the "docking" of substrates/ligands on enzymes/proteins is not an abrupt single-step event but a rather a dynamic process, influenced by the conformational dynamics of the participating biomolecules, involving multiple 'bindingunbinding' events, till the minimum-energy configuration is achieved. [39][40][41][42][43] Upon the first encounter of the DNA and the protein, electrostatic interactions induces charge-reorganization in the protein, i.e. due to the approaching negatively charge DNA electrons are repelled from the binding site in the protein (Figure 5C, panel II).…”

Section: Discussionmentioning

confidence: 99%

Electron Spin-Polarizability and Charge Dynamics in Ancient Polypeptides – Their Role in Protein Function

Vyas,

Santra,

Preeyanka

et al. 2023

Preprint

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We investigated the association of two model primordial polypeptides, each bearing an ancient and ubiquitous phosphate-binding motif, with DNA. The association rate and the amount of bound DNA relates to the electron spin-dependent polarizability of the binding protein. Contributions to protein polarizability are also made by residues that are far from the spin injection site. The spin-dependence is associated with the chirality of the proteins and is a consequence of chiral-induced spin selectivity (CISS). Since the polypeptides studied are hypothesized to be among the initial stand-alone ‘seed’ fragments from which contemporary protein domains evolved, the results suggest the importance of spin-dependent polarizability early in protein evolution. As the spin effect is a direct consequence of biopolymer homochirality, it was likely significant from even the earliest stages of biological evolution. We provide model calculations clarifying the underlying reasons for spin selectivity and estimating its impact on protein function.

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Section: Discussionmentioning

confidence: 99%

Electron Spin-Polarizability and Charge Dynamics in Ancient Polypeptides – Their Role in Protein Function

Vyas,

Santra,

Preeyanka

et al. 2023

Preprint

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“…Significant fluctuations in all three cases are observed mostly for the residues belonging to turn/coils on the enzyme surface. A loop near the His-64 residue has shown reasonable fluctuations (reported as CT21 [81] ). However, the catalytically important residues were not affected due to ligand binding/unbinding as probed along the MD trajectories.…”

Section: Stability Of the Simulated Systemmentioning

confidence: 91%

“…During its excursion through the active site channel, the orientation of the FC5 molecule is found to fluctuate parallel and perpendicular to the axis of the conical cavity. [81] Thereafter, it transiently attaches itself to various locations on the surface at an average distance of 15-20 Å from the Zn(II) ion before being stabilized in the region near site1 at a distance of 6.67 Å from the Zn(II) ion for a relatively long period between 416 and 728 ns. It is finally found to locate itself at the solvent exposed edge of the active site cavity, in the neighborhood of Gln-136.…”

Section: Ligand Dynamics Along the 1 Ms Long MD Trajectorymentioning

confidence: 99%

“…Most significant fluctuations (RMSF � 1:0 Å) are found to result from the dynamics of few common turns/coils at the N-/C-termini and surface of HCA II which persist irrespective of the trajectory length or the ligand-bound system. These include the N-terminal region (CT1 [81] ), a turn in between βa and βJ (T4 [81] ), a coil in between βA and αF (C17 [81] ), a loop between αG and βI (CT21 [81] ) and the C-terminal end (C22 [81] ). As evident from Figure 11(a) and (b), the fluctuations at the Nterminus is significantly larger for AZM-and FC5-bound HCA II when compared to the 3G1 system as shown in Figure 11(c).…”

Section: In Search Of Important Cvs Along the 1 Ms-long Trajectoriesmentioning

confidence: 99%

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A Case Study on the Use of Binding Free Energies to Screen Inhibitors of Human Carbonic Anhydrase II

Khatua¹,

Bhowmik²,

Taraphder³

2023

ChemPhysChem

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We present in this article a case study on the thermodynamics of binding to human carbonic anhydrase II (HCA II) by three well-known inhibitors, viz. (a) acetazolamide (AZM) that directly binds to the catalytic Zn(II) ion at the active site, (b) non-zinc binding 6-hydroxy-2-thioxocoumarin (FC5) (c) 2-[(S)benzylsulfinyl]benzoic acid (3G1). In each case, the crystal structure or its analogue of inhibitor-bound HCA II has been used to perform classical molecular dynamics (MD) simulation in water till 1 ms. AZM and FC5 are found to undergo repeated binding and unbinding with markedly different dynamics from the partially buried, substrate-binding hydrophobic pocket near the active site. 3G1, on the other hand, is found to remain mostly at its crystallographic binding site occluded from the active site of HCA II. The associated binding free energies ( DG bind;solv ) have been computed using the known MM/GBSA method and compared to the available experimental data. Our results show that DG bind;solv encounters several issues including limited sampling of multiple binding sites and incorrect prediction of the affinity of the chosen ligands. Possible use of the simulation results in further construction of Markov state models is also discussed.

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Dynamics of an inhibitor at and away from an out-of-active site binding location in human carbonic anhydrase II

Khatua,

Taraphder

2023

Chemical Physics Impact

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In the footsteps of an inhibitor unbinding from the active site of human carbonic anhydrase II

Cited by 3 publications

References 80 publications

Electron Spin-Polarizability and Charge Dynamics in Ancient Polypeptides – Their Role in Protein Function

Electron Spin-Polarizability and Charge Dynamics in Ancient Polypeptides – Their Role in Protein Function

A Case Study on the Use of Binding Free Energies to Screen Inhibitors of Human Carbonic Anhydrase II

Dynamics of an inhibitor at and away from an out-of-active site binding location in human carbonic anhydrase II

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