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Extending the scope of alchemical perturbation methods for ligand binding free energy calculations

Fagerberg, Eric LU (2016) KFK920 20161
Biophysical Chemistry
Abstract (Swedish)
Previously, a method for computing binding free energies between different poses of a ligand bound to a protein using alchemical perturbation was developed. The methodology is to perturb the ligand into a smaller version, common to both poses, from which the difference in free energy between poses can be computed. Here, the method is further improved by finding low-error setups for the method, by investigating different kinds of restraints put on the system during simulation and different kinds of parameters for the soft-core potential. The best low-error setup found was using a 1-1-48 soft-core potential with a water barrier and positional restraints for all the non-hydrogen atoms in the system. Instability was detected for one of the... (More)
Previously, a method for computing binding free energies between different poses of a ligand bound to a protein using alchemical perturbation was developed. The methodology is to perturb the ligand into a smaller version, common to both poses, from which the difference in free energy between poses can be computed. Here, the method is further improved by finding low-error setups for the method, by investigating different kinds of restraints put on the system during simulation and different kinds of parameters for the soft-core potential. The best low-error setup found was using a 1-1-48 soft-core potential with a water barrier and positional restraints for all the non-hydrogen atoms in the system. Instability was detected for one of the poses, this was investigated. The key to having a stable pose seems to be to understand the effect on stability of changing the Ryckaert-Bellemans parameters for a single rotatable bond. (Less)
Popular Abstract (Swedish)
Det finns utmaningar med datormodeller av läkemedel som binder till proteiner på olika sätt. Genom att göra modellen mer overklig kan osäkerheten i resultatet bli mindre.
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author
Fagerberg, Eric LU
supervisor
organization
course
KFK920 20161
year
type
H2 - Master's Degree (Two Years)
subject
keywords
biophysical chemistry, biofysikalisk kemi
language
English
id
8895770
date added to LUP
2016-12-16 14:24:01
date last changed
2017-03-03 15:03:47
@misc{8895770,
  abstract     = {Previously, a method for computing binding free energies between different poses of a ligand bound to a protein using alchemical perturbation was developed. The methodology is to perturb the ligand into a smaller version, common to both poses, from which the difference in free energy between poses can be computed. Here, the method is further improved by finding low-error setups for the method, by investigating different kinds of restraints put on the system during simulation and different kinds of parameters for the soft-core potential. The best low-error setup found was using a 1-1-48 soft-core potential with a water barrier and positional restraints for all the non-hydrogen atoms in the system. Instability was detected for one of the poses, this was investigated. The key to having a stable pose seems to be to understand the effect on stability of changing the Ryckaert-Bellemans parameters for a single rotatable bond.},
  author       = {Fagerberg, Eric},
  keyword      = {biophysical chemistry,biofysikalisk kemi},
  language     = {eng},
  note         = {Student Paper},
  title        = {Extending the scope of alchemical perturbation methods for ligand binding free energy calculations},
  year         = {2016},
}