How accurately do force fields represent protein side chain ensembles?

Petrović, Dušan; Wang, Xue; Strodel, Birgit

doi:10.1002/prot.25525

Cited by 17 publications

(16 citation statements)

References 90 publications

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“…We also note that the force field (all-atom AMBER vs. united-atom GROMOS) may play a role in the flexibility of the complex. It is in fact known that these force fields predict fairly different structural and dynamical properties for proteins 33,34 .…”

Section: Resultsmentioning

confidence: 99%

Charge transfer from the carotenoid can quench chlorophyll excitation in antenna complexes of plants

et al. 2020

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The photosynthetic apparatus of higher plants can dissipate excess excitation energy during high light exposure, by deactivating excited chlorophylls through a mechanism called nonphotochemical quenching (NPQ). However, the precise molecular details of quenching and the mechanism regulating the quenching level are still not completely understood. Focusing on the major light-harvesting complex LHCII of Photosystem II, we show that a charge transfer state involving Lutein can efficiently quench chlorophyll excitation, and reduce the excitation lifetime of LHCII to the levels measured in the deeply quenched LHCII aggregates. Through a combination of molecular dynamics simulations, multiscale quantum chemical calculations, and kinetic modeling, we demonstrate that the quenching level can be finely tuned by the protein, by regulating the energy of the charge transfer state. Our results suggest that a limited conformational rearrangement of the protein scaffold could act as a molecular switch to activate or deactivate the quenching mechanism.

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Section: Resultsmentioning

confidence: 99%

Charge transfer from the carotenoid can quench chlorophyll excitation in antenna complexes of plants

et al. 2020

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“…Following the methodology previously established by our group [4], we selected the amber99SB-ILDN as the force field of the simulations. Amber99SB-ILDN is an improved version of the amber99SB force field [43], which is widely used in MD simulations of proteins [44]. The new side-chain torsion potentials of amber99SB-ILDN are clearly improved and do not cause undesirable side effects [43].…”

Section: Methodsmentioning

confidence: 99%

“…The new side-chain torsion potentials of amber99SB-ILDN are clearly improved and do not cause undesirable side effects [43]. Amber99SB-ILDN proved to be a good choice for the MD simulation of proteins [44], since this force field accurately descript many protein structural and dynamical properties [45]. Amber99SB-ILDN is therefore recommended for the simulation of protein dynamics [43,44].…”

Section: Methodsmentioning

confidence: 99%

In silico analysis of PFN1 related to amyotrophic lateral sclerosis

2019

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Profilin 1 (PFN1) protein plays key roles in neuronal growth and differentiation, membrane trafficking, and regulation of the actin cytoskeleton. Four natural variants of PFN1 were described as related to ALS, the most common adult-onset motor neuron disorder. However, the pathological mechanism of PFN1 in ALS is not yet completely understood. The goal of this work is to thoroughly analyze the effects of the ALS-related mutations on PFN1 structure and function using computational simulations. Here, PhD-SNP, PMUT, PolyPhen-2, SIFT, SNAP, SNPS&GO, SAAP, nsSNPAnalyzer, SNPeffect4.0 and I-Mutant2.0 were used to predict the functional and stability effects of PFN1 mutations. ConSurf was used for the evolutionary conservation analysis, and GROMACS was used to perform the MD simulations. The mutations C71G, M114T, and G118V, but not E117G, were predicted as deleterious by most of the functional prediction algorithms that were used. The stability prediction indicated that the ALS-related mutations could destabilize PFN1. The ConSurf analysis indicated that the mutation C71G, M114T, E117G, and G118V occur in highly conserved positions. The MD results indicated that the studied mutations could affect the PFN1 flexibility at the actin and PLP-binding domains, and consequently, their intermolecular interactions. It may be therefore related to the functional impairment of PFN1 upon C71G, M114T, E117G and G118V mutations, and their involvement in ALS development. We also developed a database, SNPMOL ( http://www.snpmol.org/ ), containing the results presented on this paper for biologists and clinicians to exploit PFN1 and its natural variants.

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“…Both GRLBD and peptides were parameterized using the Amber14SB force field 41 , because accurately represent protein ensembles. 42 Dex was parametrized using the GAFF force field 43 after computing the point charges at the HF/6-31G* level of theory. Each complex was embedded in a TIP3P water box 44 and neutralized by adding Na + and Clions.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Sala¹,

Gunnarsson²,

Edman³

et al. 2021

Preprint

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<div>Glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the</div><div>transcription of specific genes. There is a known allosteric cross-talk between the ligand and coregulator binding</div><div>sites within the GR ligand binding domain that is crucial for the control of the functional response. However, the</div><div>molecular mechanisms underlying such an allosteric control remain elusive. Here, molecular dynamics (MD)</div><div>simulations, bioinformatic analysis and biophysical measurements are integrated to capture the structural and</div><div>dynamic features of the allosteric cross-talk within GR. We identified a network of evolutionarily conserved</div><div>residues that enables the allosteric signal transduction, in agreement with experimental data. MD simulations</div><div>clarify how such network is dynamically interconnected and offer a mechanistic explanation of how the different</div><div>peptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GR</div><div>allosteric regulation, ultimately, posing the foundation for designing novel drugs.</div>

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How accurately do force fields represent protein side chain ensembles?

Cited by 17 publications

References 90 publications

Charge transfer from the carotenoid can quench chlorophyll excitation in antenna complexes of plants

Charge transfer from the carotenoid can quench chlorophyll excitation in antenna complexes of plants

In silico analysis of PFN1 related to amyotrophic lateral sclerosis

Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

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