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Conformational Entropies and Order Parameters: Convergence, Reproducibility, and Transferability

Genheden, Samuel LU ; Akke, Mikael LU and Ryde, Ulf LU (2014) In Journal of Chemical Theory and Computation 10(1). p.432-438
Abstract
Conformational entropy provides major contributions to protein folding and functions, such as ligand binding, making it a potentially important driver of biologically relevant processes. NMR spectroscopy is a unique technique to estimate conformational entropy changes at atomic resolution, an approach that can be favorably augmented by comparisons with results from molecular dynamics (MD) simulations, for example, by generating an order-parameter-to-entropy dictionary. Here, we address critical issues pertaining to such an approach, including reproducibility, convergence, and transferability by analyzing long (380 ns -1 ms) MD trajectories obtained for five different proteins. We observe that order parameters and conformational entropies... (More)
Conformational entropy provides major contributions to protein folding and functions, such as ligand binding, making it a potentially important driver of biologically relevant processes. NMR spectroscopy is a unique technique to estimate conformational entropy changes at atomic resolution, an approach that can be favorably augmented by comparisons with results from molecular dynamics (MD) simulations, for example, by generating an order-parameter-to-entropy dictionary. Here, we address critical issues pertaining to such an approach, including reproducibility, convergence, and transferability by analyzing long (380 ns -1 ms) MD trajectories obtained for five different proteins. We observe that order parameters and conformational entropies calculated over 10-100 ns windows are typically well converged among individual MD trajectories and reproducible between pairs of independent trajectories, when calculated on a per-residue level. However, significant discrepancies sometimes arise for the total conformational entropy evaluated as the sum of the residue-specific entropies, especially in cases that involve rare transitions to alternative conformational states. Furthermore, we find that the order-parameter-to-entropy dictionary depends strongly on the protein and the sampling frequency, but much less so on the molecular dynamics force field. Thus, the transferability of the dictionary is poor between proteins but relatively good between different states (e.g., different ligand-bound complexes) of the same protein, provided that a protein-specific dictionary has been derived. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
10
issue
1
pages
432 - 438
publisher
The American Chemical Society
external identifiers
  • wos:000330142400041
  • scopus:84892565996
ISSN
1549-9618
DOI
10.1021/ct400747s
language
English
LU publication?
yes
id
bc1f0593-a859-4577-bdbf-f453df6f554d (old id 4318675)
date added to LUP
2014-02-25 12:03:12
date last changed
2017-07-23 03:15:43
@article{bc1f0593-a859-4577-bdbf-f453df6f554d,
  abstract     = {Conformational entropy provides major contributions to protein folding and functions, such as ligand binding, making it a potentially important driver of biologically relevant processes. NMR spectroscopy is a unique technique to estimate conformational entropy changes at atomic resolution, an approach that can be favorably augmented by comparisons with results from molecular dynamics (MD) simulations, for example, by generating an order-parameter-to-entropy dictionary. Here, we address critical issues pertaining to such an approach, including reproducibility, convergence, and transferability by analyzing long (380 ns -1 ms) MD trajectories obtained for five different proteins. We observe that order parameters and conformational entropies calculated over 10-100 ns windows are typically well converged among individual MD trajectories and reproducible between pairs of independent trajectories, when calculated on a per-residue level. However, significant discrepancies sometimes arise for the total conformational entropy evaluated as the sum of the residue-specific entropies, especially in cases that involve rare transitions to alternative conformational states. Furthermore, we find that the order-parameter-to-entropy dictionary depends strongly on the protein and the sampling frequency, but much less so on the molecular dynamics force field. Thus, the transferability of the dictionary is poor between proteins but relatively good between different states (e.g., different ligand-bound complexes) of the same protein, provided that a protein-specific dictionary has been derived.},
  author       = {Genheden, Samuel and Akke, Mikael and Ryde, Ulf},
  issn         = {1549-9618},
  language     = {eng},
  number       = {1},
  pages        = {432--438},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Conformational Entropies and Order Parameters: Convergence, Reproducibility, and Transferability},
  url          = {http://dx.doi.org/10.1021/ct400747s},
  volume       = {10},
  year         = {2014},
}