An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

Souza, Paulo C. T.; Thallmair, Sebastian; Marrink, Siewert J.; Mera‐Adasme, Raúl

doi:10.1021/acs.jpclett.9b02868

Cited by 49 publications

(40 citation statements)

References 47 publications

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“…Most of these issues are inherent to the process of coarse-graining, but some of these problems can be alleviated at least to some extent. For instance, protein flexibility can be greatly improved by the combination of Martini and Gō-like models 85,86 . Hydration of pockets can be modeled by the usage of smaller water beads, as it was already applied here in the A 2A R and β2AR case (see Supplementary Methods).…”

Section: Discussionmentioning

confidence: 99%

Protein–ligand binding with the coarse-grained Martini model

et al. 2020

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The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, computer-aided design of protein-ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein-ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the wellcharacterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.

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Section: Discussionmentioning

confidence: 99%

Protein–ligand binding with the coarse-grained Martini model

et al. 2020

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“…Considerable research has suggested that Cu dyshomeostasis contributes to the onset of the most common neurodegenerative disorders besides AD, including Parkinson’s disease, prion-mediated encephalopathies, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) [ 78 , 79 , 80 , 81 ]. Hence, circumstances leading to a higher or lower copper concentration can be hazardous to health, such as Menkes diseases, a genetic disorder of Cu deficiency [ 82 , 83 ].…”

Section: Introductionmentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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“…Based on contacts defined by an overlap and contacts of structural units-criterion evaluated only for the residues resolved in the crystal structure, Lennard-Jones interactions were added up to a cutoff distance of 1.1 nm (Thallmair et al, 2019). The dissociation energy of the Lennard-Jones potential was set to ε = 12.0 kJ/mol (Souza et al, 2019). In total, 541 Gō-like bonds were added for tubbyCT.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

A second PI(4,5)P₂binding site determines PI(4,5)P₂sensitivity of the tubby domain

Thallmair

Schultz

Marrink

et al. 2020

Preprint

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Phosphosinositides (PIs) are lipid signaling molecules that operate by recruiting proteins to cellular membranes via PI recognition domains. Such domains are also used widely as fluorescence-coupled biosensors for cellular PIs. For PI(4,5)P2, the dominant PI of the plasma membrane (PM), only two recognition domains have been characterized in detail and used as sensors. One of them, the tubby domain, which is conserved in the tubby-like protein (TULP) family, is essential for targeting proteins into cilia in a process involving reversible membrane association. However, the PI(4,5)P2 binding properties of tubby domains have remained enigmatic. Here we used coarse-grained molecular dynamics (MD) simulations to explore PI(4,5)P2 binding by the prototypic tubby domain (tubbyCT). While the MD simulations showed a comparatively low PI(4,5)P2 affinity of the previously described canonical binding site, they unexpectedly revealed an adjacent second binding site, consisting of a conserved cationic cluster at the protein-membrane interface. Population of this second site dramatically increased membrane association of tubbyCT. Although less specific than the canonical binding pocket, this second site preferred binding of PI(4,5)P2 over PI(4)P and phosphatidyl serine. Mutations in this site impaired PI(4,5)P2-dependent PM localization in living cells and PI(4,5)P2 interaction in silico. Thus, the second binding site essentially contributes to the effective affinity and hence PM association of the tubby domain. The two-ligand binding mode may serve to sharpen the membrane association-dissociation cycle of TULPs that underlies delivery of ciliary cargo.

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An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

Cited by 49 publications

References 47 publications

Protein–ligand binding with the coarse-grained Martini model

Protein–ligand binding with the coarse-grained Martini model

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

A second PI(4,5)P₂binding site determines PI(4,5)P₂sensitivity of the tubby domain

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An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

Cited by 49 publications

References 47 publications

Protein–ligand binding with the coarse-grained Martini model

Protein–ligand binding with the coarse-grained Martini model

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

A second PI(4,5)P2binding site determines PI(4,5)P2sensitivity of the tubby domain

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Product

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A second PI(4,5)P₂binding site determines PI(4,5)P₂sensitivity of the tubby domain