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Spectrally Resolved Estimation of Water Entropy in the Active Site of Human Carbonic Anhydrase II
- Source :
- Journal of Chemical Theory and Computation. 17:5409-5418
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- A major challenge in understanding ligand binding to biomacromolecules lies in dissecting the underlying thermodynamic driving forces at the atomic level. Quantifying the contributions of water molecules is often especially demanding, although they can play important roles in biomolecular recognition and binding processes. One example is human carbonic anhydrase II, whose active site harbors a conserved network of structural water molecules that are essential for enzymatic catalysis. Inhibitor binding disrupts this water network and changes the hydrogen-bonding patterns in the active site. Here, we use atomistic molecular dynamics simulations to compute the absolute entropy of the individual water molecules confined in the active site of hCAII using a spectrally resolved estimation (SRE) approach. The entropy decrease of water molecules that remain in the active site upon binding of a dorzolamide inhibitor is caused by changes in hydrogen bonding and stiffening of the hydrogen-bonding network. Overall, this entropy decrease is overcompensated by the gain due to the release of three water molecules from the active site upon inhibitor binding. The spectral density calculations enable the assignment of the changes to certain vibrational modes. In addition, the range of applicability of the SRE approximation is systematically explored by exploiting the gradually changing degree of immobilization of water molecules as a function of the distance to a phospholipid bilayer surface, which defines an "entropy ruler". These results demonstrate the applicability of SRE to biomolecular solvation, and we expect it to become a useful method for entropy calculations in biomolecular systems.
- Subjects :
- Entropy
Carbonic anhydrase II
Lipid Bilayers
Thiophenes
010402 general chemistry
Carbonic Anhydrase II
01 natural sciences
Molecular dynamics
Catalytic Domain
0103 physical sciences
Humans
Molecule
Physical and Theoretical Chemistry
Lipid bilayer
Sulfonamides
010304 chemical physics
biology
Chemistry
Hydrogen bond
Solvation
Water
Active site
Hydrogen Bonding
0104 chemical sciences
Computer Science Applications
Chemical physics
biology.protein
Protein Binding
Entropy (order and disorder)
Subjects
Details
- ISSN :
- 15499626 and 15499618
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of Chemical Theory and Computation
- Accession number :
- edsair.doi.dedup.....d8a6f6ab97c74ce4b7b33300f41a6a96