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  Accurate calculation of free energy changes upon amino acid mutation.

Aldeghi, M., de Groot, B. L., & Gapsys, V. (2019). Accurate calculation of free energy changes upon amino acid mutation. In T. Sikosek (Ed.), Computational Methods in Protein Evolution (pp. 19-47). New York: Springer Nature. doi:10.1007/978-1-4939-8736-8_2.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-615A-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-1AC8-F
Genre: Book Chapter

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

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Free keywords: Molecular dynamics; alchemistry; amino acid mutation; free energy calculations; hybrid structure; hybrid topology; non-equilibrium transitions; pmx
 Abstract: Molecular dynamics based free energy calculations allow for a robust and accurate evaluation of free energy changes upon amino acid mutation in proteins. In this chapter we cover the basic theoretical concepts important for the use of calculations utilizing the non-equilibrium alchemical switching methodology. We further provide a detailed step-by-step protocol for estimating the effect of a single amino acid mutation on protein thermostability. In addition, the potential caveats and solutions to some frequently encountered issues concerning the non-equilibrium alchemical free energy calculations are discussed. The protocol comprises details for the hybrid structure/topology generation required for alchemical transitions, equilibrium simulation setup, and description of the fast non-equilibrium switching. Subsequently, the analysis of the obtained results is described. The steps in the protocol are complemented with an illustrative practical application: a destabilizing mutation in the Trp cage mini protein. The concepts that are described are generally applicable. The shown example makes use of the pmx software package for the free energy calculations using Gromacs as a molecular dynamics engine. Finally, we discuss how the current protocol can readily be adapted to carry out charge-changing or multiple mutations at once, as well as large-scale mutational scans.

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Language(s): eng - English
 Dates: 2018-09-272019
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1007/978-1-4939-8736-8_2
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Title: Computational Methods in Protein Evolution
Source Genre: Book
 Creator(s):
Sikosek, T., Editor
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Publ. Info: New York : Springer Nature
Pages: 420 Volume / Issue: - Sequence Number: - Start / End Page: 19 - 47 Identifier: ISBN: 978-1-4939-8735-1

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Title: Methods in Molecular Biology
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Pages: - Volume / Issue: 1851 Sequence Number: - Start / End Page: - Identifier: -