CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures

Kuriata, Aleksander; Gierut, Aleksandra Maria; Oleniecki, Tymoteusz; Ciemny, Maciej Pawel; Koliński, Andrzej; Kurciński, Mateusz; Kmiecik, Sebastian

doi:10.1093/nar/gky356

Cited by 288 publications

(230 citation statements)

References 18 publications

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“…For a selection of mutant variants of ULK1 (F14L, N96D, A101T, A125T, R137C, R137H and D138N) that have hub-behavior, we also collected conformational ensembles using the coarse-grained approach implemented in CABS_flex 2.0 [85]. We used as starting structures for CABS_flex calculations the models generated by FoldX during the mutational scan for each of these mutations.…”

Section: Cabs_flex Ensembles Of Selected Ulk1 Mutant Variantsmentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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Autophagy is a key clearance process for the cell to recycle damaged cellular components. Autophagy is also well known for its dual role in cancer, acting as both tumor suppressor or promoter in a context-dependent way. One important upstream regulator of autophagy is the kinase ULK1. Several structures of the kinase domain of ULK1 have been solved, but a comprehensive study, including molecular dynamics, is currently missing. Also, an exhaustive description of the landscape of ULK1 cancer-related alterations is presently lacking. We here exploited the large amount of data on more than 30 cancer types through The Cancer Genome Atlas and the Recount2 initiatives to identify and analyze the atlas of ULK1 alterations in terms of gene expression and mutations. Moreover, we predicted the effects of mutations on ULK1 function and structural stability using a computational workflow accounting for protein dynamics and different layers of changes that a mutation can induce in a protein.We discovered that ULK1, along with ULK2 are down-regulated in gynecological tumors, suggesting an impairment of the upstream regulation of autophagy. In other cancer types, ULK2 can compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression level have been found for both genes. We identified 36 missense mutations of ULK1 especially in uterine, colon, stomach and lung cancer that were co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in these cancer types. Moreover, our study allowed to pinpoint that more than 50% of the mutations of ULK1 found in the cancer samples affect protein stability, which is likely to affect the cellular level and turnover of the protein. Among the damaging mutations for stability, A125T, F273V, L215P, F14L, and G12D are also predicted not to alter the functional state of the protein. Three mutations (S184F, D102N, and A28V) are predicted with the only impact on kinase activity, either modifying the functional dynamics of the protein or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended more broadly to other targets to help in the classification of mutational effects in disease, to prioritize variants for experimental validation or select the appropriate biological readouts for experiments.suggested to play essential scaffolding roles for autophagosome formation and maturation [9]. ULK1 has been reported overexpressed or downregulated in different cancer types or subtypes [25][26][27][28]. Autophagy in general has a strong association with cancer and can act with a dual role in a context-dependent way, being both tumor suppressor or promoter [29,30]. AMPK-ULK1 mediated autophagy also induces resistance against bromodomain and extraterminal domain inhibitors, which are novel epigenetic therapeutics for acute myeloid leukemia [31].So it can be a pivotal target to curb the chemotherapeutic resistance in cancers....

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Section: Cabs_flex Ensembles Of Selected Ulk1 Mutant Variantsmentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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“…CABS-flex method is dedicated for fast simulations of protein flexibility [3] [4]. CABS-flex uses a well-established CABS coarse-grained model (reviewed elsewhere [2]) as a simulation engine and merges it with tools for all-atom and simulation analysis.…”

Section: Materials 21 Cabs-flex Methodsmentioning

confidence: 99%

“…Moreover, CABS-flex method is successfully used in Aggrescan3D method [15][16][17][18] to predict the influence of protein flexibility on protein aggregation properties, and in CABS-dock method for simulations of protein flexibility during peptide molecular docking [19][20][21][22]. CABS-flex method is presently available as the CABS-flex 2.0 web server [3] (http://biocomp.chem.uw.edu.pl/CABSflex2) and the standalone package [4]. [23], which is required by CABS-flex for all-atom reconstruction from C-alpha trace of CABS models A thorough installation guide and CABS-flex issue tracker, which allows users to report any issues, can be found at CABS-flex repository.…”

Section: Materials 21 Cabs-flex Methodsmentioning

confidence: 99%

“…In this work, we present the protocols for prediction of protein structure fluctuations using CG protein models of medium-(CABS-flex) and low-resolution (SURPASS). Section 2 contains short description of CABS-flex [3,4] and SURPASS [5,6] simulation tools and their access links. Section 3 presents the protocols for fast simulations of protein structure flexibility.…”

Section: Introductionmentioning

confidence: 99%

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Protocols for fast simulations of protein structure flexibility using CABS-flex and SURPASS

Badaczewska-Dawid

Koliński

Kmiecik

2019

Preprint

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Conformational flexibility of protein structures can play an important role in protein function. The flexibility is often studied using computational methods, since experimental characterization can be difficult. Depending on protein system size; computational tools may require large computational resources or significant simplifications in the modeled systems to speed-up calculations. In this work, we present the protocols for efficient simulations of flexibility of folded protein structures that use coarse-grained simulation tools of different resolutions: medium, represented by CABS-flex, and low, represented by SUPRASS. We test the protocols using a set of 140 globular proteins and compare the results with structure fluctuations observed in MD simulations, ENM modeling and NMR ensembles. As demonstrated, CABS-flex predictions show high correlation to experimental and MD simulation data, while SURPASS is less accurate but promising in terms of future developments.

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“…Structures having 3D information were only considered. SwissDock server [49] was utilized for this purpose.…”

Section: Ligand Selection and Docking Analysismentioning

confidence: 99%

Structural analysis of the Babesia microti thioredoxin reductase: a potential drug target for babesiosis treatment

Arora¹,

Banerjee²,

Narasu³

2018

biomedicalresearch

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Babesia microti, the causative agent of human babesiosis which was endemic in United States and parts of Europe with sporadic cases in other regions is expanding its geographical range. Being a common transfusion threat, Babesia has become a cause of concern in researchers and epidemiologists. Human babesiosis is now recognized as an emerging disease and gains more attention now than ever before. Thioredoxin reductase, a promising drug target in apicomplexan parasite has been validated in several species. This study focused on in-silico analysis of physicochemical properties, functional and structural aspects of thioredoxin reductase of B. microti. Comparative modeling approach was adopted for developing the three dimensional structural model of Thioredoxin reductase of Babesia microti. The model developed was found to be of reasonably good stereo-chemical quality by structure validation servers. This study will provide valuable insights about the function and structure of the enzyme thioredoxin reductase of B. microti and aid in developing effective chemotherapeutic agents for control and treatment of Babesia.

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CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures

Cited by 288 publications

References 18 publications

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Protocols for fast simulations of protein structure flexibility using CABS-flex and SURPASS

Structural analysis of the Babesia microti thioredoxin reductase: a potential drug target for babesiosis treatment

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