| 1. |
- Hultén, Johan, et al.
(författare)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Tidskriftsartikel (refereegranskat)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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| 2. |
- Feierberg, Isabella, et al.
(författare)
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Energetics of the proposed rate-determining step of the glyoxalase I reaction
- 1999
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Ingår i: FEBS Letters. - 0014-5793 .- 1873-3468. ; 453:1-2, s. 90-94
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Tidskriftsartikel (refereegranskat)abstract
- The proposed rate-limiting step of the reaction catalyzed by glyoxalase I is the proton abstraction from the C1 carbon atom of the substrate by a glutamate residue, resulting in a high-energy enolate intermediate. This proton transfer reaction was modelled using molecular dynamics and free energy perturbation simulations, with the empirical valence bond method describing the potential energy surface of the system. The calculated rate constant for the reaction is approximately 300-1500 s(-1) with Zn2+, Mg2+ or Ca2+ bound to the active site, which agrees well with observed kinetics of the enzyme. Furthermore, the results imply that the origin of the catalytic rate enhancement is mainly associated with enolate stabilization by the metal ion.
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| 3. |
- Åqvist, Johan, et al.
(författare)
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Sugar Recognition by a Glucose/Galactose Receptor : Evaluation of Binding Energetics from Molecular Dynamics Simulations
- 1995
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 270:17, s. 9978-9981
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Tidskriftsartikel (refereegranskat)abstract
- A new theoretical method for free energy calculations is used to compute the absolute binding constants for β-D-glucose and methyl-β-D-galactoside to the periplasmic glucose/galactose receptor from Salmonella typhimurium. The computer simulation results agree well with available experimental data and make it possible to assess the sources of both the high affinity as well as the specificity for glucose. It was found that the major contribution to the binding energy comes from electrostatic interactions and particularly hydrogen bonds of the charge-dipole type. We also predict the structure of the complex with methyl-galactoside as this has not yet been experimentally determined.
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