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How to obtain statistically converged MM/GBSA results.

Genheden, Samuel LU and Ryde, Ulf LU (2010) In Journal of Computational Chemistry 31(Online 13 Jul 2009). p.837-846
Abstract
The molecular mechanics/generalized Born surface area (MM/GBSA) method has been investigated with the aim of achieving a statistical precision of 1 kJ/mol for the results. We studied the binding of seven biotin analogues to avidin, taking advantage of the fact that the protein is a tetramer with four independent binding sites, which should give the same estimated binding affinities. We show that it is not enough to use a single long simulation (10 ns), because the standard error of such a calculation underestimates the difference between the four binding sites. Instead, it is better to run several independent simulations and average the results. With such an approach, we obtain the same results for the four binding sites, and any desired... (More)
The molecular mechanics/generalized Born surface area (MM/GBSA) method has been investigated with the aim of achieving a statistical precision of 1 kJ/mol for the results. We studied the binding of seven biotin analogues to avidin, taking advantage of the fact that the protein is a tetramer with four independent binding sites, which should give the same estimated binding affinities. We show that it is not enough to use a single long simulation (10 ns), because the standard error of such a calculation underestimates the difference between the four binding sites. Instead, it is better to run several independent simulations and average the results. With such an approach, we obtain the same results for the four binding sites, and any desired precision can be obtained by running a proper number of simulations. We discuss how the simulations should be performed to optimize the use of computer time. The correlation time between the MM/GBSA energies is approximately 5 ps and an equilibration time of 100 ps is needed. For MM/GBSA, we recommend a sampling time of 20-200 ps for each separate simulation, depending on the protein. With 200 ps production time, 5-50 separate simulations are required to reach a statistical precision of 1 kJ/mol (800-8000 energy calculations or 1.5-15 ns total simulation time per ligand) for the seven avidin ligands. This is an order of magnitude more than what is normally used, but such a number of simulations is needed to obtain statistically valid results for the MM/GBSA method. (c) 2009 Wiley Periodicals, Inc. J Comput Chem 2009. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Computational Chemistry
volume
31
issue
Online 13 Jul 2009
pages
837 - 846
publisher
John Wiley & Sons
external identifiers
  • wos:000274922000015
  • pmid:19598265
  • scopus:76249085850
ISSN
1096-987X
DOI
10.1002/jcc.21366
language
English
LU publication?
yes
id
71487c85-2ad9-469a-9bcf-90da72883fb7 (old id 1453106)
date added to LUP
2009-09-01 09:22:40
date last changed
2018-06-24 04:08:52
@article{71487c85-2ad9-469a-9bcf-90da72883fb7,
  abstract     = {The molecular mechanics/generalized Born surface area (MM/GBSA) method has been investigated with the aim of achieving a statistical precision of 1 kJ/mol for the results. We studied the binding of seven biotin analogues to avidin, taking advantage of the fact that the protein is a tetramer with four independent binding sites, which should give the same estimated binding affinities. We show that it is not enough to use a single long simulation (10 ns), because the standard error of such a calculation underestimates the difference between the four binding sites. Instead, it is better to run several independent simulations and average the results. With such an approach, we obtain the same results for the four binding sites, and any desired precision can be obtained by running a proper number of simulations. We discuss how the simulations should be performed to optimize the use of computer time. The correlation time between the MM/GBSA energies is approximately 5 ps and an equilibration time of 100 ps is needed. For MM/GBSA, we recommend a sampling time of 20-200 ps for each separate simulation, depending on the protein. With 200 ps production time, 5-50 separate simulations are required to reach a statistical precision of 1 kJ/mol (800-8000 energy calculations or 1.5-15 ns total simulation time per ligand) for the seven avidin ligands. This is an order of magnitude more than what is normally used, but such a number of simulations is needed to obtain statistically valid results for the MM/GBSA method. (c) 2009 Wiley Periodicals, Inc. J Comput Chem 2009.},
  author       = {Genheden, Samuel and Ryde, Ulf},
  issn         = {1096-987X},
  language     = {eng},
  number       = {Online 13 Jul 2009},
  pages        = {837--846},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Computational Chemistry},
  title        = {How to obtain statistically converged MM/GBSA results.},
  url          = {http://dx.doi.org/10.1002/jcc.21366},
  volume       = {31},
  year         = {2010},
}