Exploring ligand dynamics in protein crystal structures with ensemble refinement
Caldararu, Octav LU ; Ekberg, Vilhelm LU ; Logan, Derek T. LU
; Oksanen, Esko
LU
and Ryde, Ulf
LU
(2021)
In Acta Crystallographica Section D: Structural Biology
77.
p.1099-1115
- Abstract
Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein-ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein-ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and... (More)
Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein-ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein-ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and atomic displacement parameters. However, since the electron-density maps are comparable and R free values are slightly increased, the original crystal structure is still a better model from a statistical point of view. On the other hand, it is shown that molecular-dynamics simulations and automatic generation of alternative conformations in crystallographic refinement confirm that the flexibility of these groups is larger than is observed in standard refinement. Moreover, the flexible groups in ensemble refinement coincide with groups that give high atomic displacement parameters or non-unity occupancy if optimized in standard refinement. Therefore, the conformational diversity indicated by ensemble refinement seems to be qualitatively correct, indicating that ensemble refinement can be an important complement to standard crystallographic refinement as a tool to discover which parts of crystal structures may show extensive flexibility and therefore are poorly described by a single conformation. However, the diversity of the ensembles is often exaggerated (probably partly owing to the rather poor force field employed) and the ensembles should not be trusted in detail.
(Less)
- author
- Caldararu, Octav
LU
; Ekberg, Vilhelm
LU
; Logan, Derek T.
LU
; Oksanen, Esko
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Ensemble refinement, Ligand dynamics, Molecular-dynamics simulations, qFit-ligand, X-ray crystal structures
- in
- Acta Crystallographica Section D: Structural Biology
- volume
- 77
- pages
- 17 pages
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:85112099634
- pmid:34342282
- ISSN
- 2059-7983
- DOI
- 10.1107/S2059798321006513
- language
- English
- LU publication?
- yes
- id
- b095bc87-0886-4428-bef5-78959e9932b2
- date added to LUP
- 2021-09-01 15:10:22
- date last changed
- 2024-06-15 15:32:41
@article{b095bc87-0886-4428-bef5-78959e9932b2,
abstract = {{<p>Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein-ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein-ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and atomic displacement parameters. However, since the electron-density maps are comparable and R free values are slightly increased, the original crystal structure is still a better model from a statistical point of view. On the other hand, it is shown that molecular-dynamics simulations and automatic generation of alternative conformations in crystallographic refinement confirm that the flexibility of these groups is larger than is observed in standard refinement. Moreover, the flexible groups in ensemble refinement coincide with groups that give high atomic displacement parameters or non-unity occupancy if optimized in standard refinement. Therefore, the conformational diversity indicated by ensemble refinement seems to be qualitatively correct, indicating that ensemble refinement can be an important complement to standard crystallographic refinement as a tool to discover which parts of crystal structures may show extensive flexibility and therefore are poorly described by a single conformation. However, the diversity of the ensembles is often exaggerated (probably partly owing to the rather poor force field employed) and the ensembles should not be trusted in detail.</p>}},
author = {{Caldararu, Octav and Ekberg, Vilhelm and Logan, Derek T. and Oksanen, Esko and Ryde, Ulf}},
issn = {{2059-7983}},
keywords = {{Ensemble refinement; Ligand dynamics; Molecular-dynamics simulations; qFit-ligand; X-ray crystal structures}},
language = {{eng}},
pages = {{1099--1115}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Acta Crystallographica Section D: Structural Biology}},
title = {{Exploring ligand dynamics in protein crystal structures with ensemble refinement}},
url = {{http://dx.doi.org/10.1107/S2059798321006513}},
doi = {{10.1107/S2059798321006513}},
volume = {{77}},
year = {{2021}},
}