title: Predicting the effects of basepair mutations in DNA-protein complexes by thermodynamic integration.
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.
authors: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Frank R
authors: FR
authors: Beierlein
authors: G Geoff
authors: GG
authors: Kneale
authors: Timothy
authors: T
authors: Clark
mesh_terms: D020029:Base Pairing; D019295:Computational Biology; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D011506:Proteins; D004247:DNA