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Assessment of enveloping distribution sampling to calculate relative free enthalpies of binding for eight netropsin–DNA duplex complexes in aqueous solution
Author(s) -
Hansen Niels,
Dolenc Jožica,
Knecht Matthias,
Riniker Sereina,
van Gunsteren Wilfred F.
Publication year - 2012
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.22879
Subject(s) - enthalpy , chemistry , free energy perturbation , netropsin , thermodynamics , aqueous solution , hamiltonian (control theory) , gibbs free energy , free base , base pair , thermodynamic integration , computational chemistry , statistical physics , mathematics , physics , molecule , dna , molecular dynamics , minor groove , mathematical optimization , biochemistry , salt (chemistry) , organic chemistry
The performance of enveloping distribution sampling (EDS) simulations to estimate free enthalpy differences associated with seven alchemical transformations of A‐T into G‐C base pairs at the netropsin binding site in the minor groove of a 13‐base pair DNA duplex in aqueous solution is evaluated. It is demonstrated that sufficient sampling can be achieved with a two‐state EDS Hamiltonian even for large perturbations such as the simultaneous transformation of up to three A‐T into three G‐C base pairs. The two parameters required to define the EDS reference state Hamiltonian are obtained automatically using a modified version of a scheme presented in earlier work. The sensitivity of the configurational sampling to a variation of these parameters is investigated in detail. Although for relatively small perturbations, that is, one base pair, the free enthalpy estimate depends only weakly on the EDS parameters, the sensitivity is stronger for the largest perturbation. Yet, EDS offers various convenient measures to evaluate the degree of sampling and thus the reliability of the free enthalpy estimate and appears to be an efficient alternative to the conventional thermodynamic integration methodology to obtain free energy differences for molecular systems. © 2012 Wiley Periodicals, Inc. J Comput Chem, 2012