English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
 
 
DownloadE-Mail
  Alchemical free energy calculations for nucleotide mutations in protein-DNA complexes.

Gapsys, V., & de Groot, B. L. (2017). Alchemical free energy calculations for nucleotide mutations in protein-DNA complexes. Journal of Chemical Theory and Computation, 13(12), 6275-6289. doi:10.1021/acs.jctc.7b00849.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-2BAA-D Version Permalink: http://hdl.handle.net/21.11116/0000-0001-2203-5
Genre: Journal Article

Files

show Files
hide Files
:
2498896.pdf (Publisher version), 5MB
Name:
2498896.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2498896_Suppl.pdf (Supplementary material), 17MB
Name:
2498896_Suppl.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Gapsys, V.1, Author              
de Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

Content

show
hide
Free keywords: -
 Abstract: Nucleotide sequence dependent interactions between proteins and DNA are responsible for a wide range of gene regulatory functions. Accurate and generalizable methods to evaluate the strength of protein-DNA binding have been long sought after. While numerous computational approaches have been developed, most of them require fitting parameters to experimental data to a certain degree, e.g. machine learning algorithms or knowledge based statistical potentials. Molecular dynamics based free energy calculations offer a robust, system independent, first principles based method to calculate free energy differences upon nucleotide mutation. We present an automated procedure to setup alchemical MD based calculations to evaluate free energy changes occurring due to a nucleotide mutation in DNA. We further use these methods to perform a large scale mutation scan comprising 397 nucleotide mutation cases in 16 protein-DNA complexes. The obtained prediction accuracy reaches 5.6 kJ/mol average unsigned deviation from experiment. Subsequently, we utilize the MD based free energy calculations to construct protein-DNA binding profiles for a zinc finger protein Zif268. The calculation results compare remarkably well with the experimentally determined binding profiles. The software automating structure and topology setup for alchemical calculations is a part of pmx package; the utilities are also made available online: http://pmx.mpibpc.mpg.de/dna_webserver.html.

Details

show
hide
Language(s): eng - English
 Dates: 2017-11-102017-12
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jctc.7b00849
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Journal of Chemical Theory and Computation
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 13 (12) Sequence Number: - Start / End Page: 6275 - 6289 Identifier: -