Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme

ACS Omega
Huishu MaKaifu Gao

Abstract

Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO2 into bicarbonate (HCO3-) and a proton (H+) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as controlling the pH level in cells and so on. However, the binding mechanism between apo-HCA II and CO2 or other ligands as well as related conformational changes remains poorly understood, and atomic investigation into it could promote our understanding of related internal physiological/pathological mechanisms. In this study, long-time atomic molecular dynamics simulations as well as the clustering and free-energy analysis were performed to reveal the dynamics of apo-HCA II as well as the mechanism upon ligand binding. Our simulations indicate that the crystallographic B-factors considerably underestimate the loop dynamics: multiple conformations can be adopted by loops 1 and 2, especially for loop 1 because loop 1 is one side of the binding pocket, and its left-to-right movement can compress or extend the binding pocket, leading to one inactive (closed) state, three intermediate (semiopen) states, and one active (open) state; CO2 cannot get into the binding pocke...Continue Reading

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Citations

Mar 9, 2021·Journal of the American Society for Mass Spectrometry·Inês C Santos, Jennifer S Brodbelt
Sep 25, 2020·Biophysical Journal·Virginija DudutienėDaumantas Matulis

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Methods Mentioned

BETA
X-ray
nuclear magnetic resonance
PCA

Software Mentioned

GROMACS
WORDOM

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