Emerging computational approaches for the study of protein allostery

Collier, Galen; Ortiz, Vanessa

doi:10.1016/j.abb.2013.07.025

Cited by 60 publications

(57 citation statements)

References 85 publications

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“…A particular application that computational studies have frequently pursued is the investigation of allostery and protein signaling at the microscopic level (9). A number of specialized methods have been proposed to address this issue (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

Ribeiro

Ortiz

2015

Biophysical Journal

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We introduce a web portal that employs network theory for the analysis of trajectories from molecular dynamics simulations. Users can create protein energy networks following methodology previously introduced by our group, and can identify residues that are important for signal propagation, as well as measure the efficiency of signal propagation by calculating the network coupling. This tool, called MDN, was used to characterize signal propagation in Escherichia coli heat-shock protein 70-kDa. Two variants of this protein experimentally shown to be allosterically active exhibit higher network coupling relative to that of two inactive variants. In addition, calculations of partial coupling suggest that this quantity could be used as part of the criteria to determine pocket druggability in drug discovery studies.

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Section: Introductionmentioning

confidence: 99%

MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

Ribeiro

Ortiz

2015

Biophysical Journal

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“…Extracting relevant allosteric pathways from simulations of proteins is a longstanding problem and a number of approaches have been developed (see e.g. [43–45] for reviews of these methods). Such methods have been applied to study various GPCRs, including the A 2A -adenosine receptor [46], β 2 AR [18], dopamine receptors [47], luteinizing hormone receptor [48], MOR [7], rhodopsin [49, 50], and 5HT 2A serotonin receptor [51, 52].…”

Section: Methodsmentioning

confidence: 99%

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

Marino

Filizola

2017

Methods in Molecular Biology

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An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important—albeit static—pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches.

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“…Results from nuclear magnetic resonance spectroscopy, computer simulations, or multiple crystal states indicate that proteins can adopt different conformations in a dynamic equilibrium [5,6], and conformational states preexist in an ensemble [7]. An energy landscape can be described as a mapping of possible conformations of the protein or spatial positions of interacting molecules in a system and as a function of corresponding energy levels on two-or three-dimensional systems.…”

Section: Understanding Of Allosterymentioning

confidence: 99%

Allosteric therapies for lung cancer

Jing

Wang

2015

Cancer Metastasis Rev

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Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.

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Emerging computational approaches for the study of protein allostery

Cited by 60 publications

References 85 publications

MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

Allosteric therapies for lung cancer

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