A conformational factorisation approach for estimating the binding free energies of macromolecules

Kenji Mochizuki, Chris S. Whittleston, Sandeep Somani, Halim Kusumaatmaja, David J. Wales

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We present a conformational factorization approach. The theory is based on a superposition partition function, decomposed as a sum over contributions from local minima. The factorisation greatly reduces the number of minima that need to be considered, by employing the same local configurations for groups that are sufficiently distant from the binding site. The theory formalises the conditions required to analyse how our definition of the binding site region affects the free energy difference between the apo and holo states. We employ basin-hopping parallel tempering to sample minima that contribute significantly to the partition function, and calculate the binding free energies within the harmonic normal mode approximation. A further significant gain in efficiency is achieved using a recently developed local rigid body framework in both the sampling and the normal mode analysis, which reduces the number of degrees of freedom. We benchmark this approach for human aldose reductase (PDB code 2INE). When varying the size of the rigid region, the free energy difference converges for factorisation of groups at a distance of 14 Å from the binding site, which corresponds to 80% of the protein being locally rigidified. This journal is

Original languageEnglish
Pages (from-to)2842-2853
Number of pages12
JournalPhysical Chemistry Chemical Physics
Volume16
Issue number7
DOIs
Publication statusPublished - Feb 21 2014
Externally publishedYes

Fingerprint

Factorization
Macromolecules
macromolecules
factorization
Free energy
estimating
free energy
Binding Sites
partitions
Aldehyde Reductase
tempering
Tempering
rigid structures
degrees of freedom
sampling
Sampling
proteins
harmonics
configurations
approximation

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Physics and Astronomy(all)

Cite this

A conformational factorisation approach for estimating the binding free energies of macromolecules. / Mochizuki, Kenji; Whittleston, Chris S.; Somani, Sandeep; Kusumaatmaja, Halim; Wales, David J.

In: Physical Chemistry Chemical Physics, Vol. 16, No. 7, 21.02.2014, p. 2842-2853.

Research output: Contribution to journalArticle

Mochizuki, K, Whittleston, CS, Somani, S, Kusumaatmaja, H & Wales, DJ 2014, 'A conformational factorisation approach for estimating the binding free energies of macromolecules', Physical Chemistry Chemical Physics, vol. 16, no. 7, pp. 2842-2853. https://doi.org/10.1039/c3cp53537a
Mochizuki, Kenji ; Whittleston, Chris S. ; Somani, Sandeep ; Kusumaatmaja, Halim ; Wales, David J. / A conformational factorisation approach for estimating the binding free energies of macromolecules. In: Physical Chemistry Chemical Physics. 2014 ; Vol. 16, No. 7. pp. 2842-2853.
@article{c4e1394b2ad840b38e25138ca33bd99b,
title = "A conformational factorisation approach for estimating the binding free energies of macromolecules",
abstract = "We present a conformational factorization approach. The theory is based on a superposition partition function, decomposed as a sum over contributions from local minima. The factorisation greatly reduces the number of minima that need to be considered, by employing the same local configurations for groups that are sufficiently distant from the binding site. The theory formalises the conditions required to analyse how our definition of the binding site region affects the free energy difference between the apo and holo states. We employ basin-hopping parallel tempering to sample minima that contribute significantly to the partition function, and calculate the binding free energies within the harmonic normal mode approximation. A further significant gain in efficiency is achieved using a recently developed local rigid body framework in both the sampling and the normal mode analysis, which reduces the number of degrees of freedom. We benchmark this approach for human aldose reductase (PDB code 2INE). When varying the size of the rigid region, the free energy difference converges for factorisation of groups at a distance of 14 {\AA} from the binding site, which corresponds to 80{\%} of the protein being locally rigidified. This journal is",
author = "Kenji Mochizuki and Whittleston, {Chris S.} and Sandeep Somani and Halim Kusumaatmaja and Wales, {David J.}",
year = "2014",
month = "2",
day = "21",
doi = "10.1039/c3cp53537a",
language = "English",
volume = "16",
pages = "2842--2853",
journal = "Physical Chemistry Chemical Physics",
issn = "1463-9076",
publisher = "Royal Society of Chemistry",
number = "7",

}

TY - JOUR

T1 - A conformational factorisation approach for estimating the binding free energies of macromolecules

AU - Mochizuki, Kenji

AU - Whittleston, Chris S.

AU - Somani, Sandeep

AU - Kusumaatmaja, Halim

AU - Wales, David J.

PY - 2014/2/21

Y1 - 2014/2/21

N2 - We present a conformational factorization approach. The theory is based on a superposition partition function, decomposed as a sum over contributions from local minima. The factorisation greatly reduces the number of minima that need to be considered, by employing the same local configurations for groups that are sufficiently distant from the binding site. The theory formalises the conditions required to analyse how our definition of the binding site region affects the free energy difference between the apo and holo states. We employ basin-hopping parallel tempering to sample minima that contribute significantly to the partition function, and calculate the binding free energies within the harmonic normal mode approximation. A further significant gain in efficiency is achieved using a recently developed local rigid body framework in both the sampling and the normal mode analysis, which reduces the number of degrees of freedom. We benchmark this approach for human aldose reductase (PDB code 2INE). When varying the size of the rigid region, the free energy difference converges for factorisation of groups at a distance of 14 Å from the binding site, which corresponds to 80% of the protein being locally rigidified. This journal is

AB - We present a conformational factorization approach. The theory is based on a superposition partition function, decomposed as a sum over contributions from local minima. The factorisation greatly reduces the number of minima that need to be considered, by employing the same local configurations for groups that are sufficiently distant from the binding site. The theory formalises the conditions required to analyse how our definition of the binding site region affects the free energy difference between the apo and holo states. We employ basin-hopping parallel tempering to sample minima that contribute significantly to the partition function, and calculate the binding free energies within the harmonic normal mode approximation. A further significant gain in efficiency is achieved using a recently developed local rigid body framework in both the sampling and the normal mode analysis, which reduces the number of degrees of freedom. We benchmark this approach for human aldose reductase (PDB code 2INE). When varying the size of the rigid region, the free energy difference converges for factorisation of groups at a distance of 14 Å from the binding site, which corresponds to 80% of the protein being locally rigidified. This journal is

UR - http://www.scopus.com/inward/record.url?scp=84892728136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892728136&partnerID=8YFLogxK

U2 - 10.1039/c3cp53537a

DO - 10.1039/c3cp53537a

M3 - Article

AN - SCOPUS:84892728136

VL - 16

SP - 2842

EP - 2853

JO - Physical Chemistry Chemical Physics

JF - Physical Chemistry Chemical Physics

SN - 1463-9076

IS - 7

ER -