scholarly journals The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

2021 ◽  
Vol 22 (21) ◽  
pp. 11529
Author(s):  
Suman Samantray ◽  
Olujide O. Olubiyi ◽  
Birgit Strodel
Keyword(s):  
Structural Parameters ◽  
Energy Landscape ◽  
Md Simulations ◽  
Structural Heterogeneity ◽  
Conformational Flexibility ◽  
Chloride Ions ◽  
Free Energy Landscape ◽  
Structural Flexibility ◽  
Dynamical Features ◽  
The Relationship

The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility.

scholarly journals Revealing Free Energy Landscape from MD Data via Conditional Angle Partition Tree

2021 ◽  
Author(s):  
Hangjin Jiang ◽  
Xuhui Huang ◽  
Han Li ◽  
Wing H Wong ◽  
Xiaodan Fan
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Dynamic Structure ◽  
Md Simulations ◽  
Free Energy Landscape ◽  
Partition Tree ◽  
Protein Protein Interaction ◽  
Geometric Similarity ◽  
The Hierarchical Structure ◽  
Alanine Dipeptide

Deciphering the free energy landscape of biomolecular structure space is crucial for understanding many complex molecular processes, such as protein-protein interaction, RNA folding, and protein folding. A major source of current dynamic structure data is Molecular Dynamics (MD) simulations. Several methods have been proposed to investigate the free energy landscape from MD data, but all of them rely on the assumption that kinetic similarity is associated with global geometric similarity, which may lead to unsatisfactory results. In this paper, we proposed a new method called Conditional Angle Partition Tree to reveal the hierarchical free energy landscape by correlating local geometric similarity with kinetic similarity. Its application on the benchmark alanine dipeptide MD data showed a much better performance than existing methods in exploring and understanding the free energy landscape. We also applied it to the MD data of Villin HP35. Our results are more reasonable on various aspects than those from other methods and very informative on the hierarchical structure of its energy landscape.

scholarly journals Multi-Level DBSCAN: A Hierarchical Density-Based Clustering Method for Analyzing Molecular Dynamics Simulation Trajectories

2021 ◽  
Author(s):  
Song Liu ◽  
Siqin Cao ◽  
Michael Alexander SUAREZ VASQUEZ ◽  
Eshani C Goonetillek ◽  
Xuhui Huang
Keyword(s):  
Free Energy ◽  
Level Density ◽  
Energy Landscape ◽  
Md Simulations ◽  
Metastable States ◽  
Dynamics Simulation ◽  
Free Energy Landscape ◽  
Islet Amyloid ◽  
Structural Details ◽  
Multi Level

Molecular Dynamic (MD) simulations have been extensively used as a powerful tool to investigate dynamics of biological molecules in recent decades. Generally, MD simulations generate high-dimensional data that is very hard to visualize and comprehend. As a result, clustering algorithms have been commonly used to reduce the dimensionality of MD data with the key benefit being their ability to reduce the dimensionality of MD data without prior knowledge of structural details or dynamic mechanisms. In this paper, we propose a new algorithm, the Multi-Level Density-Based Spatial Clustering of Applications with Noise (ML-DBSCAN), which combines the clustering results at different resolution of density levels to obtain the hierarchical structure of the free energy landscape and the metastable state assignment. At relatively low resolutions, the ML-DBSCAN can efficiently detect high population regions that contain all metastable states, while at higher resolutions, the ML-DBSCAN can find all metastable states and structural details of the free energy landscape. We demonstrate the powerfulness of the ML-DBSCAN in generating metastable states with a particle moving in a Mexican hat-like potential, and four peptide and protein examples are used to demonstrate how hierarchical structures of free energy landscapes can be found. Furthermore, we developed a GPU implementation of the ML-DBSCAN, which allows the algorithm to handle larger MD datasets and be up to two orders of magnitude faster than the CPU implementation. We demonstrate the power of the ML-DBSCAN on MD simulation datasets of five systems: a 2D-potential, alanine dipeptide, β-hairpin Tryptophan Zipper 2 (Trpzip2), Human Islet Amyloid Polypeptide (hIAPP), and Maltose Binding Protein (MBP). Our code is available at https://github.com/liusong299/ML-DBSCAN.

scholarly journals Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1273
Author(s):  
Ahmed L. Alaofi ◽  
Mudassar Shahid
Keyword(s):  
Free Energy ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Energy Landscape ◽  
Principal Component ◽  
Md Simulations ◽  
Free Energy Landscape ◽  
Binding Motif ◽  
Converting Enzyme

The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral–host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.

Structural Flexibility in Crystalline Coordination Polymers: A Journey Along the Underlying Free Energy Landscape

2021 ◽  
Author(s):  
Claire Hobday ◽  
Gregor Kieslich
Keyword(s):  
Free Energy ◽  
Coordination Polymers ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Structural Flexibility ◽  
Chemical Interactions ◽  
Network Geometry

Crystalline coordination polymers are a chemical diverse material platform that provide control over network geometry and chemical interactions, harbouring a wealth of phenomena of large scientific and technological relevance. The...

Revisiting the High-Pressure Properties of the Metal-Organic Frameworks ZIF-8 and ZIF-67

2020 ◽  
Author(s):  
Pia Vervoorts ◽  
Stefan Burger ◽  
Karina Hemmer ◽  
Gregor Kieslich
Keyword(s):  
High Pressure ◽  
State Of The Art ◽  
Energy Landscape ◽  
Structural Flexibility ◽  
Zeolitic Imidazolate Frameworks ◽  
Stimuli Responsive ◽  
X Ray Diffraction ◽  
X Ray ◽  
Open Questions ◽  
Metal Organic

The zeolitic imidazolate frameworks ZIF-8 and ZIF-67 harbour a series of fascinating stimuli responsive properties. Looking at their responsitivity to hydrostatic pressure as stimulus, open questions exist regarding the isotropic compression with non-penetrating pressure transmitting media. By applying a state-of-the-art high-pressure powder X-ray diffraction setup, we revisit the high-pressure behaviour of ZIF-8 and ZIF-67 up to <i>p</i> = 0.4 GPa in small pressure increments. We observe a drastic, reversible change of high-pressure powder X-ray diffraction data at <i>p</i> = 0.3 GPa, discovering large volume structural flexibility in ZIF-8 and ZIF-67. Our results imply a shallow underlying energy landscape in ZIF-8 and ZIF-67, an observation that might point at rich polymorphism of ZIF-8 and ZIF-67, similar to ZIF-4(Zn).<br>

Revisiting the High-Pressure Properties of the Metal-Organic Frameworks ZIF-8 and ZIF-67

2020 ◽  
Author(s):  
Pia Vervoorts ◽  
Stefan Burger ◽  
Karina Hemmer ◽  
Gregor Kieslich
Keyword(s):  
High Pressure ◽  
State Of The Art ◽  
Energy Landscape ◽  
Structural Flexibility ◽  
Zeolitic Imidazolate Frameworks ◽  
Stimuli Responsive ◽  
X Ray Diffraction ◽  
X Ray ◽  
Open Questions ◽  
Metal Organic

The zeolitic imidazolate frameworks ZIF-8 and ZIF-67 harbour a series of fascinating stimuli responsive properties. Looking at their responsitivity to hydrostatic pressure as stimulus, open questions exist regarding the isotropic compression with non-penetrating pressure transmitting media. By applying a state-of-the-art high-pressure powder X-ray diffraction setup, we revisit the high-pressure behaviour of ZIF-8 and ZIF-67 up to <i>p</i> = 0.4 GPa in small pressure increments. We observe a drastic, reversible change of high-pressure powder X-ray diffraction data at <i>p</i> = 0.3 GPa, discovering large volume structural flexibility in ZIF-8 and ZIF-67. Our results imply a shallow underlying energy landscape in ZIF-8 and ZIF-67, an observation that might point at rich polymorphism of ZIF-8 and ZIF-67, similar to ZIF-4(Zn).<br>

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>

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