An approximate but efficient method to calculate free energy trends by computer simulation: Application to dihydrofolate reductase-inhibitor complexes

Gerber, PR, Mark, AE and Vangunsteren, WF (1993) An approximate but efficient method to calculate free energy trends by computer simulation: Application to dihydrofolate reductase-inhibitor complexes. Journal of Computer-Aided Molecular Design, 7 3: 305-323. doi:10.1007/BF00125505


Author Gerber, PR
Mark, AE
Vangunsteren, WF
Title An approximate but efficient method to calculate free energy trends by computer simulation: Application to dihydrofolate reductase-inhibitor complexes
Journal name Journal of Computer-Aided Molecular Design   Check publisher's open access policy
ISSN 0920-654X
Publication date 1993-01-01
Sub-type Article (original research)
DOI 10.1007/BF00125505
Volume 7
Issue 3
Start page 305
End page 323
Total pages 19
Publisher Kluwer Academic Publishers
Language eng
Subject 1313 Molecular Medicine
Abstract Derivatives of free energy differences have been calculated by molecular dynamics techniques. The systems under study were ternary complexes of Trimethoprim (TMP) with dihydrofolate reductases of E. coli and chicken liver, containing the cofactor NADPH. Derivatives are taken with respect to modification of TMP, with emphasis on altering the 3-, 4- and 5-substituents of the phenyl ring. A linear approximation allows the encompassing of a whole set of modifications in a single simulation, as opposed to a full perturbation calculation, which requires a separate simulation for each modification. In the case considered here, the proposed technique requires a factor of 1000 less computing effort than a full free energy perturbation calculation. For the linear approximation to yield a significant result, one has to find ways of choosing the perturbation evolution, such that the initial trend mirrors the full calculation. The generation of new atoms requires a careful treatment of the singular terms in the non-bonded interaction. The result can be represented by maps of the changed molecule, which indicate whether complex formation is favoured under movement of partial charges and change in atom polarizabilities. Comparison with experimental measurements of inhibition constants reveals fair agreement in the range of values covered. However, detailed comparison fails to show a significant correlation. Possible reasons for the most pronounced deviations are given.
Keyword DHFR-inhibitor complexes
Free energy differences
Linear approximation
Molecular dynamics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: ResearcherID Downloads
Scopus Import - Archived
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 39 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 41 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 04 Feb 2016, 01:01:53 EST by System User