Enhanced conformational sampling technique provides an energy landscape view of large-scale protein conformational transitions

2016 ◽  
Vol 18 (42) ◽  
pp. 29170-29182 ◽  
Author(s):  
Qiang Shao
Keyword(s):  
Configuration Space ◽  
Conformational Changes ◽  
In Silico ◽  
Quantitative Data ◽  
Large Scale ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Conformational Transitions ◽  
Conformational Sampling

A novel in silico approach (NMA–ITS) is introduced to rapidly and effectively sample the configuration space and give quantitative data for exploring the conformational changes of proteins.

scholarly journals Metastable Intermediates as Stepping Stones on the Maturation Pathways of Viral Capsids

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Giovanni Cardone ◽  
Robert L. Duda ◽  
Naiqian Cheng ◽  
Lili You ◽  
James F. Conway ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Structural Changes ◽  
Energy Landscape ◽  
Potential Hazard ◽  
Stepping Stones ◽  
Scanning Calorimetry ◽  
Conformational Effects ◽  
Capsid Maturation ◽  
Capsid Integrity

ABSTRACT As they mature, many capsids undergo massive conformational changes that transform their stability, reactivity, and capacity for DNA. In some cases, maturation proceeds via one or more intermediate states. These structures represent local minima in a rich energy landscape that combines contributions from subunit folding, association of subunits into capsomers, and intercapsomer interactions. We have used scanning calorimetry and cryo-electron microscopy to explore the range of capsid conformations accessible to bacteriophage HK97. To separate conformational effects from those associated with covalent cross-linking (a stabilization mechanism of HK97), a cross-link-incompetent mutant was used. The mature capsid Head I undergoes an endothermic phase transition at 60°C in which it shrinks by 7%, primarily through changes in its hexamer conformation. The transition is reversible, with a half-life of ~3 min; however, >50% of reverted capsids are severely distorted or ruptured. This observation implies that such damage is a potential hazard of large-scale structural changes such as those involved in maturation. Assuming that the risk is lower for smaller changes, this suggests a rationalization for the existence of metastable intermediates: that they serve as stepping stones that preserve capsid integrity as it switches between the radically different conformations of its precursor and mature states. IMPORTANCE Large-scale conformational changes are widespread in virus maturation and infection processes. These changes are accompanied by the release of conformational free energy as the virion (or fusogenic glycoprotein) switches from a precursor state to its mature state. Each state corresponds to a local minimum in an energy landscape. The conformational changes in capsid maturation are so radical that the question arises of how maturing capsids avoid being torn apart. Offering proof of principle, severe damage is inflicted when a bacteriophage HK97 capsid reverts from the (nonphysiological) state that it enters when heated past 60°C. We suggest that capsid proteins have been selected in part by the criterion of being able to avoid sustaining collateral damage as they mature. One way of achieving this—as with the HK97 capsid—involves breaking the overall transition down into several smaller steps in which the risk of damage is reduced.

scholarly journals GM-DockZn: a geometry matching-based docking algorithm for zinc proteins

2020 ◽  
Vol 36 (13) ◽  
pp. 4004-4011
Author(s):  
Kai Wang ◽  
Nan Lyu ◽  
Hongjuan Diao ◽  
Shujuan Jin ◽  
Tao Zeng ◽  
...  
Keyword(s):  
Large Scale ◽  
Protein Structures ◽  
Sampling Technique ◽  
Superior Performance ◽  
Ligand Docking ◽  
Supplementary Information ◽  
Conformational Sampling ◽  
Ligand Complex ◽  
Coordination Systems ◽  
Zinc Coordination

Abstract Motivation Molecular docking is a widely used technique for large-scale virtual screening of the interactions between small-molecule ligands and their target proteins. However, docking methods often perform poorly for metalloproteins due to additional complexity from the three-way interactions among amino-acid residues, metal ions and ligands. This is a significant problem because zinc proteins alone comprise about 10% of all available protein structures in the protein databank. Here, we developed GM-DockZn that is dedicated for ligand docking to zinc proteins. Unlike the existing docking methods developed specifically for zinc proteins, GM-DockZn samples ligand conformations directly using a geometric grid around the ideal zinc-coordination positions of seven discovered coordination motifs, which were found from the survey of known zinc proteins complexed with a single ligand. Results GM-DockZn has the best performance in sampling near-native poses with correct coordination atoms and numbers within the top 50 and top 10 predictions when compared to several state-of-the-art techniques. This is true not only for a non-redundant dataset of zinc proteins but also for a homolog set of different ligand and zinc-coordination systems for the same zinc proteins. Similar superior performance of GM-DockZn for near-native-pose sampling was also observed for docking to apo-structures and cross-docking between different ligand complex structures of the same protein. The highest success rate for sampling nearest near-native poses within top 5 and top 1 was achieved by combining GM-DockZn for conformational sampling with GOLD for ranking. The proposed geometry-based sampling technique will be useful for ligand docking to other metalloproteins. Availability and implementation GM-DockZn is freely available at www.qmclab.com/ for academic users. Supplementary information Supplementary data are available at Bioinformatics online.

Physics of Biomolecular Recognition and Conformational Dynamics

2021 ◽  
Author(s):  
Wen-Ting Chu ◽  
Zhiqiang Yan ◽  
Xiakun Chu ◽  
Xiliang Zheng ◽  
Zuojia Liu ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Conformational Changes ◽  
Large Scale ◽  
Energy Landscape ◽  
Conformational Dynamics ◽  
Experimental Investigations ◽  
Biomolecular Recognition ◽  
Energy Landscape Theory ◽  
Landscape Theory ◽  
Underlying Mechanisms

Abstract Biomolecular recognition usually leads to the formation of binding complexes, often accompanied by large-scale conformational changes. This process is fundamental to biological functions at the molecular and cellular levels. Uncovering the physical mechanisms of biomolecular recognition and quantifying the key biomolecular interactions are vital to understand these functions. The recently developed energy landscape theory has been successful in quantifying recognition processes and revealing the underlying mechanisms. Recent studies have shown that in addition to affinity, specificity is also crucial for biomolecular recognition. The proposed physical concept of intrinsic specificity based on the underlying energy landscape theory provides a practical way to quantify the specificity. Optimization of affinity and specificity can be adopted as a principle to guide the evolution and design of molecular recognition. This approach can also be used in practice for drug discovery using multidimensional screening to identify lead compounds. The energy landscape topography of molecular recognition is important for revealing the underlying flexible binding or binding-folding mechanisms. In this review, we first introduce the energy landscape theory for molecular recognition and then address four critical issues related to biomolecular recognition and conformational dynamics: (1) specificity quantification of molecular recognition; (2) evolution and design in molecular recognition; (3) flexible molecular recognition; (4) chromosome structural dynamics. The results described here and the discussions of the insights gained from the energy landscape topography can provide valuable guidance for further computational and experimental investigations of biomolecular recognition and conformational dynamics.

scholarly journals Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion

2017 ◽  
Vol 114 (42) ◽  
pp. 11157-11162 ◽  
Author(s):  
Alexandra C. Walls ◽  
M. Alejandra Tortorici ◽  
Joost Snijder ◽  
Xiaoli Xiong ◽  
Berend-Jan Bosch ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Large Scale ◽  
Energy Landscape ◽  
Limited Proteolysis ◽  
Subunit Vaccines ◽  
Virus Family ◽  
The Past ◽  
Structural Framework ◽  
Molecular Events ◽  
Evolutionary Relatedness

The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. The coronavirus spike (S) glycoprotein initiates infection by promoting fusion of the viral and cellular membranes through conformational changes that remain largely uncharacterized. Here we report the cryoEM structure of a coronavirus S glycoprotein in the postfusion state, showing large-scale secondary, tertiary, and quaternary rearrangements compared with the prefusion trimer and rationalizing the free-energy landscape of this conformational machine. We also biochemically characterized the molecular events associated with refolding of the metastable prefusion S glycoprotein to the postfusion conformation using limited proteolysis, mass spectrometry, and single-particle EM. The observed similarity between postfusion coronavirus S and paramyxovirus F structures demonstrates that a conserved refolding trajectory mediates entry of these viruses and supports the evolutionary relatedness of their fusion subunits. Finally, our data provide a structural framework for understanding the mode of neutralization of antibodies targeting the fusion machinery and for engineering next-generation subunit vaccines or inhibitors against this medically important virus family.

Is economic inequality a universal evil?

2019 ◽  
pp. 91-106 ◽  
Author(s):  
Rostislav I. Kapeliushnikov
Keyword(s):  
Quantitative Data ◽  
Large Scale ◽  
Economic Inequality ◽  
The State ◽  
Fair Play ◽  
Left Wing ◽  
Ordinary People ◽  
The Public ◽  
Discursive Power ◽  
A Current

Using published estimates of inequality for two countries (Russia and USA) the paper demonstrates that inequality measuring still remains in the state of “statistical cacophony”. Under this condition, it seems at least untimely to pass categorical normative judgments and offer radical political advice for governments. Moreover, the mere practice to draw normative conclusions from quantitative data is ethically invalid since ordinary people (non-intellectuals) tend to evaluate wealth and incomes as admissible or inadmissible not on the basis of their size but basing on whether they were obtained under observance or violations of the rules of “fair play”. The paper concludes that a current large-scale ideological campaign of “struggle against inequality” has been unleashed by left-wing intellectuals in order to strengthen even more their discursive power over the public.

Determination of Base Flipping Free Energy Landscapes from Nonequilibrium Stratification

2019 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Umbrella Sampling ◽  
Energy Simulation ◽  
Nonlinear Dependence ◽  
Free Energy Landscape ◽  
Convergence Criterion ◽  
Base Flipping ◽  
Convergence Behavior

<p>Correct calculation of the variation of free energy upon base flipping is crucial in understanding the dynamics of DNA systems. The free energy landscape along the flipping pathway gives the thermodynamic stability and the flexibility of base-paired states. Although numerous free energy simulations are performed in the base flipping cases, no theoretically rigorous nonequilibrium techniques are devised and employed to investigate the thermodynamics of base flipping. In the current work, we report a general nonequilibrium stratification scheme for efficient calculation of the free energy landscape of base flipping in DNA duplex. We carefully monitor the convergence behavior of the equilibrium sampling based free energy simulation and the nonequilibrium stratification and determine the empirical length of time blocks required for converged sampling. Comparison between the performances of equilibrium umbrella sampling and nonequilibrium stratification is given. The results show that nonequilibrium free energy simulation is able to give similar accuracy and efficiency compared with the equilibrium enhanced sampling technique in the base flipping cases. We further test a convergence criterion we previously proposed and it comes out that the convergence behavior determined by this criterion agrees with those given by the time-invariant behavior of PMF and the nonlinear dependence of standard deviation on the sample size. </p>

Supporting teachers in their use of ICT in teaching mathematics: What kind of support is necessary and when is it required?

2018 ◽  
Vol 6 (7) ◽  
pp. 1-8
Author(s):  
Benard Litali Ashiono
Keyword(s):  
Public Schools ◽  
Primary Schools ◽  
Quantitative Data ◽  
Mixed Methods Research ◽  
Sampling Technique ◽  
Simple Random Sampling ◽  
Teaching Mathematics ◽  
Second Phase ◽  
Grade One ◽  
Supporting Teachers

This article reports on a study that was carried out to establish determinants of ICT integration in mathematics teaching and learning. This paper focuses on the kind of support teachers require to effectively use ICT in teaching mathematics. An exploratory sequential mixed methods research design was employed to conduct this study in which quantitative data was initially collected in the first phase. Qualitative data was then collected in the second phase to explain the quantitative data collected in the initial phase. The study targeted all the teachers teaching in lower grades in both private and public schools. A sample size of 40 lower primary schools were purposively selected based on the availability of ICT tools for instructional purposes in those schools. Three teachers teaching in grade one, two and three were then selected using simple random sampling technique especially in cases where more than three teachers existed. Teacher Questionnaire, Teacher Interview Protocol and Observation Protocol were used to collect data. Data was analyzed qualitatively using descriptive phenomenological analysis in which data transcriptions were divided into themes and sub-themes related to phenomena under study. The findings of the study revealed that there was a significant relationship between supporting teachers’ use of ICT in the classroom and their actual use of ICT in teaching mathematics. The study findings however revealed that teachers teaching lower grades in Mombasa, Kenya were not adequately supported in their use of ICT in teaching mathematics. It was recommended that teachers must be granted adequate support in their use of ICT in teaching mathematics.

scholarly journals Identification of Efficient Sampling Techniques for Probabilistic Voltage Stability Analysis of Renewable-Rich Power Systems

Energies ◽  
2021 ◽  
Vol 14 (8) ◽  
pp. 2328
Author(s):  
Mohammed Alzubaidi ◽  
Kazi N. Hasan ◽  
Lasantha Meegahapola ◽  
Mir Toufikur Rahman
Keyword(s):  
Monte Carlo ◽  
Stability Analysis ◽  
Power Systems ◽  
Large Scale ◽  
Voltage Stability ◽  
Sampling Technique ◽  
Coefficient Of Determination ◽  
Sampling Techniques ◽  
Quasi Monte Carlo ◽  
Efficient Sampling

This paper presents a comparative analysis of six sampling techniques to identify an efficient and accurate sampling technique to be applied to probabilistic voltage stability assessment in large-scale power systems. In this study, six different sampling techniques are investigated and compared to each other in terms of their accuracy and efficiency, including Monte Carlo (MC), three versions of Quasi-Monte Carlo (QMC), i.e., Sobol, Halton, and Latin Hypercube, Markov Chain MC (MCMC), and importance sampling (IS) technique, to evaluate their suitability for application with probabilistic voltage stability analysis in large-scale uncertain power systems. The coefficient of determination (R2) and root mean square error (RMSE) are calculated to measure the accuracy and the efficiency of the sampling techniques compared to each other. All the six sampling techniques provide more than 99% accuracy by producing a large number of wind speed random samples (8760 samples). In terms of efficiency, on the other hand, the three versions of QMC are the most efficient sampling techniques, providing more than 96% accuracy with only a small number of generated samples (150 samples) compared to other techniques.

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