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Free energy screening of small ligands binding to an artificial protein cavity (2000)

Banba, Shinichi ; Brooks, Charles L.

College Park, Md. : American Institute of Physics (AIP)

The Journal of Chemical Physics 113 (2000), S. 3423-3433

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ISSN: 1089-7690

Source: AIP Digital Archive

Topics: Physics , Chemistry and Pharmacology

Notes: The λ-dynamics simulation method was used to study the binding of 10 five-member ring heterocycle derivatives to an artificial cavity created inside cytochrome C peroxidase by mutagenesis. Application of λ dynamics using a multiple topology approach resulted in trapping in local minima. To extend the method to these cases, a new restraining potential was devised and added to the extended Hamiltonian. Two approximations were introduced in order to estimate the binding free energy within small simulation times using this potential: (a) The entropy terms related to the restraining potential are assumed to cancel, due to the similarity of the ligands. (b) The restraining potential calculated from the coordinates of the environmental atoms during a λ-dynamics simulation is assumed to be equal to that of the average coordinates. Relatively short λ-dynamics simulations with this restraining potential successfully yielded reasonable estimates of the binding affinity of the ligands as compared with both experimental data and free energy perturbation calculations. Long time λ-dynamics simulations with a ten-ligand system revealed that better ligands tend to have small statistical errors, which is appropriate for screening out the plausible ligands from all candidates. Furthermore, short time λ-dynamics simulations with ten identical ligands demonstrated that sufficient precision was achieved for putative discovery of tight binding ligands or guests. © 2000 American Institute of Physics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.1287147

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Protein folding With a little help... (2002)

Brooks, Charles L.

[s.l.] : Nature Publishing Group

Nature 420 (2002), S. 33-34

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ISSN: 1476-4687

Source: Nature Archives 1869 - 2009

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Notes: [Auszug] From a cast of thousands, and the experiments of a few, a new combination of computer simulation and experiment to investigate protein folding has emerged. This work, described by Snow et al. on page 102 of this issue, shows that the key events in the folding of a small artificial protein ...