Biophysical Journal
Volume 101, Issue 5, 7 September 2011, Pages 1130-1138
Journal home page for Biophysical Journal

Article
Predicting the Effects of Basepair Mutations in DNA-Protein Complexes by Thermodynamic Integration

https://doi.org/10.1016/j.bpj.2011.07.003Get rights and content
Under an Elsevier user license
open archive

Abstract

Thermodynamically rigorous free energy methods in principle allow the exact computation of binding free energies in biological systems. Here, we use thermodynamic integration together with molecular dynamics simulations of a DNA-protein complex to compute relative binding free energies of a series of mutants of a protein-binding DNA operator sequence. A guanine-cytosine basepair that interacts strongly with the DNA-binding protein is mutated into adenine-thymine, cytosine-guanine, and thymine-adenine. It is shown that basepair mutations can be performed using a conservative protocol that gives error estimates of ∼10% of the change in free energy of binding. Despite the high CPU-time requirements, this work opens the exciting opportunity of being able to perform basepair scans to investigate protein-DNA binding specificity in great detail computationally.

Cited by (0)