Insights on the acetylated NF-κB transcription factor complex with DNA from molecular dynamics simulations

The nuclear factor‐κB (NF‐κB) is a DNA sequence‐specific regulator of many important biological processes, whose activity is modulated by enzymatic acetylation. In one of the best functionally characterized NF‐κB complexes, the p50/p65 heterodimer, acetylation of K221 at p65 causes a decrease of DNA dissociation rate, whilst the acetylation of K122 and K123, also at p65, markedly decreases the binding affinity for DNA. By means of molecular dynamics simulations based on the X‐ray structure of the p50/p65 complex with DNA, we provide insights on the structural determinants of the acetylated complexes in aqueous solution. Lysine acetylation involves the loss of favorable electrostatic interactions between DNA and NF‐κB, which is partially compensated by the reduction of the desolvation free‐energy of the two binding partners. Acetylation at both positions K122 and K123 is associated with a decrease of the electrostatic potential at the p65/DNA interface, which is only partially counterbalanced by an increase of the local Na+ concentration. It induces the disruption of base‐specific and nonspecific interactions between DNA and NF‐κB and it is consistent with the observed decrease of binding affinity. In contrast, acetylation at position K221 results in the loss of nonspecific protein–DNA interactions, but the DNA recognition sites are not affected. In addition, the loss of protein–DNA interactions is likely to be counterbalanced by an increase of the configurational entropy of the complex, which provides, at a speculative level, a justification for the observed decrease of NF‐κB/DNA dissociation rate. Proteins 2012. © 2012 Wiley Periodicals, Inc.