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Free energy calculations for the relative binding affinity between DNA and λ‐repressor
Author(s) -
Saito Minoru,
Sarai Akinori
Publication year - 2003
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10333
Subject(s) - repressor , thymine , lambda , chemistry , dna , free energy perturbation , binding energy , crystallography , van der waals force , interaction energy , molecular dynamics , stereochemistry , molecule , physics , computational chemistry , atomic physics , biochemistry , quantum mechanics , gene , organic chemistry , transcription factor
The change in the binding free energy between DNA and λ‐repressor resulting from a base substitution, thymine (T)→deoxyuracil (abbreviated as U), was evaluated by the free energy perturbation method on the basis of molecular dynamics simulations for the DNA–λ‐repressor complex in water with all degrees of freedom and including long‐range Coulomb interactions. The binding free energy change that we calculated (1.47 ± 0.40 kcal/mol) was in good agreement with an experimental value (1.8 kcal/mol). We clarified why the small difference between T and U (CH 3 in T is replaced with H in U) caused such a significant change in the binding free energy: The substitution of CH 3 in T with H in U lowered the dissociated‐state free energy level due to the gain of the hydration free energy. Furthermore, the T→U substitution raised the free energy level in the associated state due to the loss of the favored van der Waals (vdW) interactions with the λ‐repressor amino acid residues. In other words, the amino acid residues of λ‐repressor can recognize the CH 3 in T through the vdW interactions with the CH 3 . This recognition is enhanced in a water environment, because the hydrophobic CH 3 prefers the amino acid residues of λ‐repressor to water molecules. Proteins 2003;52:129–136. © 2003 Wiley‐Liss, Inc.