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  Comment on "Deficiencies in molecular dynamics simulation-based prediction of protein-DNA binding free energy landscapes"

Gapsys, V., Khabiri, M., de Groot, B. L., & Freddolino, P. L. (2020). Comment on "Deficiencies in molecular dynamics simulation-based prediction of protein-DNA binding free energy landscapes". The Journal of Physical Chemistry B, 124(6), 1115-1123. doi:10.1021/acs.jpcb.8b04187.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-B7C6-D Version Permalink: http://hdl.handle.net/21.11116/0000-0005-B7CA-9
Genre: Journal Article

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Gapsys, V.1, Author              
Khabiri, M., Author
de Groot, B. L.1, Author              
Freddolino, P. L., Author
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1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 Abstract: Sequence-specific DNA binding transcription factors play an essential role in the transcriptional regulation of all organisms. The development of reliable in silico methods to predict the binding affinity landscapes of transcription factors thus promises to provide rapid screening of transcription factor specificities and, at the same time, yield valuable insight into the atomistic details of the interactions driving those specificities. Recent literature has reported highly discrepant results on the current ability of state-of-the-art atomistic molecular dynamics simulations to reproduce experimental binding free energy landscapes for transcription factors. Here, we resolve one important discrepancy by noting that in the case of alchemical free energy calculations involving base pair mutations, a common convention used in improving end point convergence of mixed potentials in fact can lead to erroneous results. The underlying cause for inaccurate double free energy difference estimates is specific to the particular implementation of the alchemical transformation protocol. Using the Gromacs simulation package, which is not affected by this issue, we obtain free energy landscapes in agreement with the experimental measurements; equivalent results are obtained for a small set of test cases with a modified version of the AMBER package. Our findings provide a consistent and optimistic outlook on the current state of prediction of protein-DNA binding free energy interactions using molecular dynamics simulations and an important precaution for appropriate end point handling in a broad range of free energy calculations.

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Language(s): eng - English
 Dates: 2020-02
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jpcb.8b04187
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Title: The Journal of Physical Chemistry B
Source Genre: Journal
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Pages: - Volume / Issue: 124 (6) Sequence Number: - Start / End Page: 1115 - 1123 Identifier: -