Linked Life Data

7538591

Source:http://linkedlifedata.com/resource/pubmed/id/7538591

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1995-6-21
pubmed:abstractText
We use the thermodynamic integration technique to calculate the free energy associated with the Tyr82-->Phe82 mutation (Y82F) in the protein FKBP-12, both free and bound to known inhibitor FK506 (tacrolimis). We find that the net difference in free energy for the two changes is 0.85 kcal/mol, with the binding of FK506 relatively more favorable for the native protein than the mutant. This net energy compares very favorably with the experimentally measured value of 0.60 kcal/mol. The results indicate that the relatively better binding of FK506 to the native protein is driven by the favorable entropy associated with the release of water molecules from the protein when the ligand binds. For a variety of reasons, modest size of the system, smallness of the change being examined, rapid convergence of the ensemble that needs to be determined and use of statistical estimates to control sampling, we have been able to carry out atypically reliable and reproducible free energy calculations for this protein system. Free energy changes for the two simulations (Y82F FKBP-12/FK506 and Y82F FKBP-12) have been calculated a total of eight times each, to compare a variety of different methodological choices and to ensure that the results are statistically significant. Detailed analysis of the free energy results has been carried out, and indicates that even when applicable, deconvolution of the total free energy into components can be very difficult, that the statistical error estimates can give a reasonable bound on the error in a simulation, and that one must be careful to use the same simulation protocol in all simulations being compared.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2836
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
248
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
696-717
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Determination of the differential effects of hydrogen bonding and water release on the binding of FK506 to native and Tyr82-->Phe82 FKBP-12 proteins using free energy simulations.
pubmed:affiliation
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139-4211, USA.
pubmed:publicationType
Journal Article