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.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Beierlein FR,Kneale GG,Clark Tdoi
10.1016/j.bpj.2011.07.003subject
Has Abstractpub_date
2011-09-07 00:00:00pages
1130-8issue
5eissn
0006-3495issn
1542-0086pii
S0006-3495(11)00830-7journal_volume
101pub_type
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