QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, J. C.; Freddolino, Peter L.; Schulten, Klaus

doi:10.1038/srep26536

Cited by 186 publications

(174 citation statements)

References 61 publications

(73 reference statements)

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“…These structures were then used as templates to derive the homology models that were further refined with molecular dynamics (MD) simulations. Equilibration for 100 ns was performed using NAMD 37 through its QwikMD interface 38 (see Supplemental Figure S2, S3 and S4). Comparison of the aligned structures (Supplemental Figure S5 A) reveals that all seven cohesins of ScaA show a similar general fold.…”

Section: Resultsmentioning

confidence: 99%

Combining in Vitro and in Silico Single-Molecule Force Spectroscopy to Characterize and Tune Cellulosomal Scaffoldin Mechanics

et al. 2017

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Cellulosomes are poly-protein machineries that efficiently degrade cellulosic material. Crucial to their function are scaffolds consisting of highly homologous cohesin domains, which serve a dual role by coordinating a multiplicity of enzymes as well as anchoring the microbe to its substrate. Here we combined two approaches to elucidate the mechanical properties of the main scaffold ScaA of Acetivibrio cellulolyticus. A newly developed parallelized onepot in vitro transcription-translation and protein pulldown protocol enabled high-throughput atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) measurements of all cohesins from ScaA with a single cantilever, thus promising improved relative force comparability. Albeit very similar in sequence, the hanging cohesins showed considerably lower unfolding forces than the bridging cohesins, which are subjected to force when the microbe is anchored to its substrate. Additionally, all-atom steered molecular dynamics (SMD) simulations on homology models offered insight into the process of cohesin unfolding under force. Based on the differences among the individual force propagation pathways and their associated correlation communities, we designed mutants to tune the mechanical stability of the weakest hanging cohesin. The proposed mutants were tested in a second high-throughput AFM SMFS experiment revealing that in one case a single alanine to glycine point mutation suffices to more than double the mechanical stability. In summary, we have successfully characterized the force induced unfolding behaviour of all cohesins from the scaffoldin ScaA, as well as revealed how small changes in sequence can have large effects on force resilience in cohesin domains. Our strategy provides an efficient way to test and improve the mechanical integrity of protein domains in general.

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Section: Resultsmentioning

confidence: 99%

Combining in Vitro and in Silico Single-Molecule Force Spectroscopy to Characterize and Tune Cellulosomal Scaffoldin Mechanics

et al. 2017

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“…To obtain the final atomic rat models, the best fitting yeast structures for each class were used as templates for comparative modeling and real-space structure refinement (Goh et al, 2016). MDFF simulations were prepared using QwikMD (Ribeiro et al, 2016), analyzed with VMD (Humphrey et al, 1996), and carried out with NAMD (Phillips et al, 2005). …”

Section: Star Methodsmentioning

confidence: 99%

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Guo

Lehmer

Martínez-Sánchez

et al. 2018

Cell

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Summary Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here we address the elusive link between these phenomena employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.

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“…The L1788R mutated FLNa16-17, G1834R and S1902R mutated FLNb16-17 were generated by mutating the corresponding amino acids in silico in FLNa16-17 and FLNb16-17 atomic detailed structures, respectively, following the protocols described in QwikMD 41 . Systems were then solvated and the net charge of the protein was neutralized using sodium atoms as counter-ions, which were randomly arranged in the solvent.…”

Section: Methodsmentioning

confidence: 99%

Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing

Seppälä

Bernardi

Haataja

et al. 2017

Sci Rep

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Cells’ ability to sense mechanical cues in their environment is crucial for fundamental cellular processes, leading defects in mechanosensing to be linked to many diseases. The actin cross-linking protein Filamin has an important role in the conversion of mechanical forces into biochemical signals. Here, we reveal how mutations in Filamin genes known to cause Larsen syndrome and Frontometaphyseal dysplasia can affect the structure and therefore function of Filamin domains 16 and 17. Employing X-ray crystallography, the structure of these domains was first solved for the human Filamin B. The interaction seen between domains 16 and 17 is broken by shear force as revealed by steered molecular dynamics simulations. The effects of skeletal dysplasia associated mutations of the structure and mechanosensing properties of Filamin were studied by combining various experimental and theoretical techniques. The results showed that Larsen syndrome associated mutations destabilize or even unfold domain 17. Interestingly, those Filamin functions that are mediated via domain 17 interactions with other proteins are not necessarily affected as strongly interacting peptide binding to mutated domain 17 induces at least partial domain folding. Mutation associated to Frontometaphyseal dysplasia, in turn, transforms 16–17 fragment from compact to an elongated form destroying the force-regulated domain pair.

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QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

Cited by 186 publications

References 61 publications

Combining in Vitro and in Silico Single-Molecule Force Spectroscopy to Characterize and Tune Cellulosomal Scaffoldin Mechanics

Combining in Vitro and in Silico Single-Molecule Force Spectroscopy to Characterize and Tune Cellulosomal Scaffoldin Mechanics

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing

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