scholarly journals Using AlphaFold to predict the impact of single mutations on protein stability and function

2021 ◽  
Author(s):  
Marina A Pak ◽  
Karina A Markhieva ◽  
Mariia S Novikova ◽  
Dmitry S Petrov ◽  
Ilya S Vorobyev ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Stability ◽  
Structure Prediction ◽  
Large Scale ◽  
3D Structure ◽  
Three Dimensional ◽  
Single Mutation ◽  
Before And After ◽  
And Function ◽  
The Impact

AlphaFold changed the field of structural biology by achieving three-dimensional (3D) structure prediction from protein sequence at experimental quality. The astounding success even led to claims that the protein folding problem is "solved". However, protein folding problem is more than just structure prediction from sequence. Presently, it is unknown if the AlphaFold-triggered revolution could help to solve other problems related to protein folding. Here we assay the ability of AlphaFold to predict the impact of single mutations on protein stability (ΔΔG) and function. To study the question we extracted metrics from AlphaFold predictions before and after single mutation in a protein and correlated the predicted change with the experimentally known ΔΔG values. Additionally, we correlated the AlphaFold predictions on the impact of a single mutation on structure with a large scale dataset of single mutations in GFP with the experimentally assayed levels of fluorescence. We found a very weak or no correlation between AlphaFold output metrics and change of protein stability or fluorescence. Our results imply that AlphaFold cannot be immediately applied to other problems or applications in protein folding.

scholarly journals Best templates outperform homology models in predicting the impact of mutations on protein stability

2021 ◽  
Author(s):  
Marina A Pak ◽  
Dmitry N Ivankov
Keyword(s):  
Protein Folding ◽  
Protein Stability ◽  
3D Structure ◽  
Three Dimensional ◽  
Homology Model ◽  
3D Protein Structure ◽  
3D Structures ◽  
Stability Change ◽  
The Impact ◽  
Homology Models

Motivation: Prediction of protein stability change upon mutation (∆∆G) is crucial for facilitating protein engineering and understanding of protein folding principles. Robust prediction of protein folding free energy change requires the knowledge of protein three-dimensional (3D) structure. Unfortunately, protein 3D structure is not always available. In this case, one can still predict the protein stability change by constructing a homology model of the protein; however, the accuracy of homology model-based ∆∆G predictions is unknown. The perspectives of using 3D structures of the best templates are also unclear. Results: To investigate these questions, we used the most popular and accurate publicly available tools: FoldX for stability change prediction and I-Tasser for homology modeling. We found that both homology models and best templates worsen the ∆∆G prediction, with best templates performing 1.5 times better than homology models. For AlphaFold models, we also found that the best templates seem to outperform protein models. Our findings imply using the 3D structures of the best templates for ∆∆G prediction if the 3D protein structure is unavailable.

Three-dimensional imaging and physiology of live neurons and glia: Confocal light and correlative high-voltage Electron Microscopy

1993 ◽  
Vol 51 ◽  
pp. 162-163
Author(s):  
J.N. Turner ◽  
D.H. Szarowski ◽  
W. Shain ◽  
M. Davis-Cox ◽  
D.O. Carpenter ◽  
...  
Keyword(s):  
Large Scale ◽  
Culture Media ◽  
Shape Change ◽  
Complex Function ◽  
3D Structure ◽  
Three Dimensional ◽  
Electron Microscopic ◽  
High Voltage Electron Microscopy ◽  
Voltage Electron ◽  
And Function

Correlating physiologic measures with three-dimensional (3D) imaging at the light and electron microscopic levels is a powerful combination of methods for studying the structure and function of biological systems. Neurobiology is an ideal field for the application of these methods because neurons and glia have complex and extensive 3D structure, and their physiology is under intense study. Neurons, such as those studied here from Aplysia, can be more than 100 μm in diameter, and glia undergo large scale 3D shape change as a function of a number of physiologic parameters. The ability to accurately quantitate the 3D structure, volume and surface area of live neurons and glia is important to our understanding of the complex function of these cells.Neurons were isolated from the major ganglia of juvenile Aplysia Californica and glia were obtained from long term cultures of LRM 55 cells or as primary isolates from rats. Cultures were exposed to Dil dissolved in DMSO with or without 20% Pluronic F-127 and added to the culture media. The imaging instrument was an Olympus IMT-2 and a Bio-Rad MRC-600.

scholarly journals PremPS: Predicting the impact of missense mutations on protein stability

2020 ◽  
Vol 16 (12) ◽  
pp. e1008543
Author(s):  
Yuting Chen ◽  
Haoyu Lu ◽  
Ning Zhang ◽  
Zefeng Zhu ◽  
Shuqin Wang ◽  
...  
Keyword(s):  
Protein Stability ◽  
Protein Design ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Predictive Performance ◽  
Computational Method ◽  
Single Mutation ◽  
Missense Mutations ◽  
Benchmark Datasets ◽  
The Impact

Computational methods that predict protein stability changes induced by missense mutations have made a lot of progress over the past decades. Most of the available methods however have very limited accuracy in predicting stabilizing mutations because existing experimental sets are dominated by mutations reducing protein stability. Moreover, few approaches could consistently perform well across different test cases. To address these issues, we developed a new computational method PremPS to more accurately evaluate the effects of missense mutations on protein stability. The PremPS method is composed of only ten evolutionary- and structure-based features and parameterized on a balanced dataset with an equal number of stabilizing and destabilizing mutations. A comprehensive comparison of the predictive performance of PremPS with other available methods on nine benchmark datasets confirms that our approach consistently outperforms other methods and shows considerable improvement in estimating the impacts of stabilizing mutations. A protein could have multiple structures available, and if another structure of the same protein is used, the predicted change in stability for structure-based methods might be different. Thus, we further estimated the impact of using different structures on prediction accuracy, and demonstrate that our method performs well across different types of structures except for low-resolution structures and models built based on templates with low sequence identity. PremPS can be used for finding functionally important variants, revealing the molecular mechanisms of functional influences and protein design. PremPS is freely available at https://lilab.jysw.suda.edu.cn/research/PremPS/, which allows to do large-scale mutational scanning and takes about four minutes to perform calculations for a single mutation per protein with ~ 300 residues and requires ~ 0.4 seconds for each additional mutation.

scholarly journals 3DIV update for 2021: a comprehensive resource of 3D genome and 3D cancer genome

2020 ◽  
Vol 49 (D1) ◽  
pp. D38-D46
Author(s):  
Kyukwang Kim ◽  
Insu Jang ◽  
Mooyoung Kim ◽  
Jinhyuk Choi ◽  
Min-Seo Kim ◽  
...  
Keyword(s):  
Cell Line ◽  
Large Scale ◽  
Three Dimensional ◽  
Cancer Cell Line ◽  
Cancer Genome ◽  
Structural Variations ◽  
3D Genome ◽  
Tightly Coupled ◽  
Regulatory Effects ◽  
The Impact

Abstract Three-dimensional (3D) genome organization is tightly coupled with gene regulation in various biological processes and diseases. In cancer, various types of large-scale genomic rearrangements can disrupt the 3D genome, leading to oncogenic gene expression. However, unraveling the pathogenicity of the 3D cancer genome remains a challenge since closer examinations have been greatly limited due to the lack of appropriate tools specialized for disorganized higher-order chromatin structure. Here, we updated a 3D-genome Interaction Viewer and database named 3DIV by uniformly processing ∼230 billion raw Hi-C reads to expand our contents to the 3D cancer genome. The updates of 3DIV are listed as follows: (i) the collection of 401 samples including 220 cancer cell line/tumor Hi-C data, 153 normal cell line/tissue Hi-C data, and 28 promoter capture Hi-C data, (ii) the live interactive manipulation of the 3D cancer genome to simulate the impact of structural variations and (iii) the reconstruction of Hi-C contact maps by user-defined chromosome order to investigate the 3D genome of the complex genomic rearrangement. In summary, the updated 3DIV will be the most comprehensive resource to explore the gene regulatory effects of both the normal and cancer 3D genome. ‘3DIV’ is freely available at http://3div.kr.

The Importance of Similarity: How Gender Congruence Matters for the Impact of Leadership Training

2021 ◽  
pp. 009539972110642
Author(s):  
Trine H. Fjendbo ◽  
Christian B. Jacobsen ◽  
Seung-Ho An
Keyword(s):  
Leadership Training ◽  
Large Scale ◽  
Leadership Behaviors ◽  
Leadership Behavior ◽  
Female Gender ◽  
Perceived Leadership ◽  
Scale Field ◽  
Before And After ◽  
Large Scale Field ◽  
The Impact

Leadership training is key to promoting more active leadership, but the effects of leadership training can depend on the gender context. Gender congruence between manager and employee can affect how the manager employs leadership behaviors adapted from training and how employees perceive leadership behavior. Quantitative data on 474 managers’ 4,833 employees before and after a large-scale field experiment with leadership training enable us to examine changes in employee-perceived leadership following training. The results show that gender congruence between manager and employee is associated with stronger leadership training effects on employee-perceived leadership behaviors. Female gender congruence shows the most pronounced effects.

scholarly journals Impact of the first COVID-19 shelter-in-place order in the United States on emergency department utilization, Marin County, California

2020 ◽  
Author(s):  
Brett R. Bayles ◽  
Michaela F George ◽  
Haylea Hannah ◽  
Patti Culross ◽  
Rochelle R. Ereman ◽  
...  
Keyword(s):  
United States ◽  
San Francisco ◽  
Large Scale ◽  
Temporal Dynamics ◽  
The United States ◽  
Emergency Department Utilization ◽  
Marin County ◽  
Before And After ◽  
Ed Visits ◽  
The Impact

Background: The first shelter-in-place (SIP) order in the United States was issued across six counties in the San Francisco Bay Area to reduce the impact of COVID-19 on critical care resources. We sought to assess the impact of this large-scale intervention on emergency departments (ED) in Marin County, California. Methods: We conducted a retrospective descriptive and trend analysis of all ED visits in Marin County, California from January 1, 2018 to May 4, 2020 to quantify the temporal dynamics of ED utilization before and after the March 17, 2020 SIP order. Results: The average number of ED visits per day decreased by 52.3% following the SIP order compared to corresponding time periods in 2018 and 2019. Both respiratory and non-respiratory visits declined, but this negative trend was most pronounced for non-respiratory admissions. Conclusions: The first SIP order to be issued in the United States in response to COVID-19 was associated with a significant reduction in ED utilization in Marin County.

scholarly journals Weighing trees with lasers: advances, challenges and opportunities

2018 ◽  
Vol 8 (2) ◽  
pp. 20170048 ◽  
Author(s):  
M. I. Disney ◽  
M. Boni Vicari ◽  
A. Burt ◽  
K. Calders ◽  
S. L. Lewis ◽  
...  
Keyword(s):  
Laser Scanning ◽  
Large Scale ◽  
Three Dimensional ◽  
Point Clouds ◽  
3D Models ◽  
Tree Form ◽  
Form And Function ◽  
Challenges And Opportunities ◽  
And Function ◽  
Non Destructive

Terrestrial laser scanning (TLS) is providing exciting new ways to quantify tree and forest structure, particularly above-ground biomass (AGB). We show how TLS can address some of the key uncertainties and limitations of current approaches to estimating AGB based on empirical allometric scaling equations (ASEs) that underpin all large-scale estimates of AGB. TLS provides extremely detailed non-destructive measurements of tree form independent of tree size and shape. We show examples of three-dimensional (3D) TLS measurements from various tropical and temperate forests and describe how the resulting TLS point clouds can be used to produce quantitative 3D models of branch and trunk size, shape and distribution. These models can drastically improve estimates of AGB, provide new, improved large-scale ASEs, and deliver insights into a range of fundamental tree properties related to structure. Large quantities of detailed measurements of individual 3D tree structure also have the potential to open new and exciting avenues of research in areas where difficulties of measurement have until now prevented statistical approaches to detecting and understanding underlying patterns of scaling, form and function. We discuss these opportunities and some of the challenges that remain to be overcome to enable wider adoption of TLS methods.

A Predictive Energy Landscape Model of Metamorphic Protein Conformational Specificity

2021 ◽  
Author(s):  
James O. Wrabl ◽  
Keila Voortman-Sheetz ◽  
Vincent J. Hilser
Keyword(s):  
Amino Acid ◽  
Structure Prediction ◽  
Large Scale ◽  
Energy Landscape ◽  
Thermodynamic Approach ◽  
High Identity ◽  
Denatured State ◽  
Metamorphic Protein ◽  
The Stability ◽  
The Impact

'Metamorphic' proteins challenge state-of-the-art structure prediction methods reliant on amino acid similarity. Unfortunately, this obviates a more effective thermodynamic approach necessary to properly evaluate the impact of amino acid changes on the stability of two different folds. A vital capability of such a thermodynamic approach would be the quantification of the free energy differences between 1) the energy landscape minima of each native fold, and 2) each fold and the denatured state. Here we develop an energetic framework for conformational specificity, based on an ensemble description of protein thermodynamics. This energetic framework was able to successfully recapitulate the structures of high-identity engineered sequences experimentally shown to adopt either Streptococcus protein GA or GB folds, demonstrating that this approach indeed reflected the energetic determinants of fold. Residue-level decomposition of the conformational specificity suggested several testable hypotheses, notably among them that fold-switching could be affected by local de-stabilization of the populated fold at positions sensitive to equilibrium perturbation. Since this ensemble-based compatibility framework is applicable to any structure and any sequence, it may be practically useful for the future targeted design, or large-scale proteomic detection, of novel metamorphic proteins.

scholarly journals Energy conservation by retrofitting of dwellings

2019 ◽  
Vol 111 ◽  
pp. 03010
Author(s):  
Imrich Sánka ◽  
Dušan Petráš
Keyword(s):  
Large Scale ◽  
Thermal Environment ◽  
Winter Season ◽  
Residential Building ◽  
Indoor Environmental Quality ◽  
Air Exchange Rate ◽  
Energy Auditing ◽  
Before And After ◽  
The Impact

This article investigates the impact of energy renovation on the indoor environmental quality of apartment building during heating season. The study was performed in one residential building before and after its renovation. Energy auditing and classification of the selected building into energy classes were carried out. Additionally, evaluation of indoor air quality was performed using objective measurements and subjective survey. Thermal environment and concentration of CO2 was measured in bedrooms. Higher concentrations of CO2 was observed in the residential building after its renovation. The concentrations of CO2, in some cases exceeded the recommended maximum limits, especially after implementing of energy saving measures on the building. The average air exchange rate was visible higher before renovation of the building. The current study indicates that large-scale of renovations may reduce the quality of the indoor environment in many apartments, especially in the winter season.

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