A Robotics Approach to Enhance Conformational Sampling of Proteins

2012 ◽  
Author(s):  
Juan Cortés ◽  
Ibrahim Al-Bluwi
Keyword(s):  
Monte Carlo ◽  
Computational Methods ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Biological Macromolecules ◽  
Dynamics And Function ◽  
Living Organisms ◽  
Dynamics Simulations ◽  
And Function ◽  
The Relationship

Proteins are biological macromolecules that play essential roles in living organisms. Furthermore, the study of proteins and their function is of interest in other fields in addition to biology, such as pharmacology and biotechnology. Understanding the relationship between protein structure, dynamics and function is indispensable for advances in all these areas. This requires a combination of experimental and computational methods, whose development is the object of very active interdisciplinary research. In such a context, this paper presents a technique to enhance conformational sampling of proteins carried out with computational methods such as molecular dynamics simulations or Monte Carlo methods. Our approach is based on a mechanistic representation of proteins that enables the application of efficient methods originating from robotics. The paper explains the generalities of the approach, and gives details on its application to devise Monte Carlo move classes. Results show the good performance of the method for sampling the conformational space of different types of proteins.

scholarly journals CoDNaS-RNA: a database of Conformational Diversity in the Native State of RNA

2020 ◽  
Author(s):  
Martín González Buitrón ◽  
Ronaldo Romario Tunque Cahui ◽  
Emilio García Ríos ◽  
Layla Hirsh ◽  
María Silvina Fornasari ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Structural Features ◽  
Rna Structures ◽  
Rna Molecules ◽  
Functional Annotations ◽  
Public Resource ◽  
Conformational Diversity ◽  
Dynamics And Function ◽  
And Function ◽  
The Relationship

AbstractConformational changes in RNA native ensembles are central to fulfill many of their biological roles. Systematic knowledge of the extent and possible modulators of this conformational diversity is desirable to better understand the relationship between RNA dynamics and function.We have developed CoDNaS-RNA as the first database of conformational diversity in RNA molecules. Known RNA structures are retrieved and clustered to identify alternative conformers of each molecule. Pairwise structural comparisons within each cluster allows to measure the variability of the molecule. Additional data on structural features, molecular interactions and functional annotations are provided. CoDNaS-RNA is implemented as a public resource that can be of much interest for computational and bench scientists alike.AvailabilityCoDNaS-RNA is freely accessible at http://ufq.unq.edu.ar/[email protected]

scholarly journals Entropic effects enable life at extreme temperatures

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw4783 ◽  
Author(s):  
Young Hun Kim ◽  
Geoffray Leriche ◽  
Karthik Diraviyam ◽  
Takaoki Koyanagi ◽  
Kaifu Gao ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Elevated Temperatures ◽  
Membrane Integrity ◽  
Membrane Dynamics ◽  
Extreme Temperatures ◽  
Molecular Interpretation ◽  
Dynamics And Function ◽  
Membrane Spanning ◽  
Dynamics Simulations ◽  
And Function

Maintaining membrane integrity is a challenge at extreme temperatures. Biochemical synthesis of membrane-spanning lipids is one adaptation that organisms such as thermophilic archaea have evolved to meet this challenge and preserve vital cellular function at high temperatures. The molecular-level details of how these tethered lipids affect membrane dynamics and function, however, remain unclear. Using synthetic monolayer-forming lipids with transmembrane tethers, here, we reveal that lipid tethering makes membrane permeation an entropically controlled process that helps to limit membrane leakage at elevated temperatures relative to bilayer-forming lipid membranes. All-atom molecular dynamics simulations support a view that permeation through membranes made of tethered lipids reduces the torsional entropy of the lipids and leads to tighter lipid packing, providing a molecular interpretation for the increased transition-state entropy of leakage.

scholarly journals Effects of α-tubulin acetylation on microtubule structure and stability

2019 ◽  
Vol 116 (21) ◽  
pp. 10366-10371 ◽  
Author(s):  
Lisa Eshun-Wilson ◽  
Rui Zhang ◽  
Didier Portran ◽  
Maxence V. Nachury ◽  
Daniel B. Toso ◽  
...  
Keyword(s):  
Conformational Sampling ◽  
Conformational Ensembles ◽  
Microtubule Stabilization ◽  
Flexible Loop ◽  
Tubulin Acetylation ◽  
Microtubule Stability ◽  
Cryo Electron Microscopy ◽  
Conformational Landscape ◽  
Dynamics Simulations ◽  
And Function

Acetylation of K40 in α-tubulin is the sole posttranslational modification to mark the luminal surface of microtubules. It is still controversial whether its relationship with microtubule stabilization is correlative or causative. We have obtained high-resolution cryo-electron microscopy (cryo-EM) reconstructions of pure samples of αTAT1-acetylated and SIRT2-deacetylated microtubules to visualize the structural consequences of this modification and reveal its potential for influencing the larger assembly properties of microtubules. We modeled the conformational ensembles of the unmodified and acetylated states by using the experimental cryo-EM density as a structural restraint in molecular dynamics simulations. We found that acetylation alters the conformational landscape of the flexible loop that contains αK40. Modification of αK40 reduces the disorder of the loop and restricts the states that it samples. We propose that the change in conformational sampling that we describe, at a location very close to the lateral contacts site, is likely to affect microtubule stability and function.

scholarly journals Effects of α-tubulin acetylation on microtubule structure and stability

2019 ◽  
Author(s):  
Lisa Eshun-Wilson ◽  
Rui Zhang ◽  
Didier Portran ◽  
Maxence Nachury ◽  
Dan Toso ◽  
...  
Keyword(s):  
Conformational Sampling ◽  
Post Translational Modification ◽  
Conformational Ensembles ◽  
Microtubule Stabilization ◽  
Tubulin Acetylation ◽  
Microtubule Stability ◽  
Cryo Electron Microscopy ◽  
Conformational Landscape ◽  
Dynamics Simulations ◽  
And Function

ABSTRACTAcetylation of K40 in α-tubulin is the sole post-translational modification to mark the luminal surface of microtubules. It is still controversial whether its relationship with microtubule stabilization is correlative or causative. We have obtained high-resolution cryo-electron microscopy reconstructions of pure samples of αTAT1-acetylated and SIRT2-deacetylated microtubules to visualize the structural consequences of this modification and reveal its potential for influencing the larger assembly properties of microtubules. We modeled the conformational ensembles of the unmodified and acetylated states by using the experimental cryo-EM density as the structural restraint in molecular dynamics simulations. We found that acetylation alters the conformational landscape of the flexible loop that contains αK40. Modification of αK40 reduces the disorder of the loop and restricts the states that it samples. We propose that the change in conformational sampling that we describe, at a location very close to the lateral contacts site, is likely to affect microtubule stability and function.

Conformational Flexibilities and Solvation Properties of Insulin in Aromatic Amino Acid Solutions: A Molecular Dynamics Study Using CHARMM Drude Polarizable Model

2021 ◽  
pp. 1-14
Author(s):  
Santanu Santra ◽  
Madhurima Jana
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Aromatic Amino Acids ◽  
Solvation Shell ◽  
Polarizable Force Field ◽  
Amino Acid Solutions ◽  
Living Organisms ◽  
Dynamics Simulations ◽  
And Function ◽  
Formed Hydrogen

Aromatic amino acids (AAA) play a crucial role in the structure and function of proteins. A higher level of AAA causes several diseases, controls insulin levels. In this work, we carried out atomistic molecular dynamics simulations by using CHARMM Drude polarizable force field to investigate the conformational properties of insulin monomer in 2M phe, tyr, trp solutions as well as in pure aqueous solution to compare the relative changes of protein conformations, its solvation properties and the interactions of the free AAA with insulin. Although insulin’s native folded form was intact in all the solutions within the simulation length scale, we observed that the protein is a little more flexible and less compact in phe solution than in tyr/trp solutions. The free AAAs identified to self-aggregate around the protein surface and form clusters of different sizes. They interacted with insulin, significantly through cation/anion–[Formula: see text] and [Formula: see text]–[Formula: see text] stacking, and partly through hydrogen bonded interactions. Among the three, trp was prone to interact through cation–[Formula: see text] interactions while phe and tyr interacted through [Formula: see text]–[Formula: see text] stacking with insulin. Despite a significant number of free AAA molecules in the solvation shell, insulin was observed to be sufficiently hydrated and formed hydrogen bonds with water. Some of our findings agreed with the available experimental results that establish the reliability of the chosen force field. Our findings would interpret the interactions between the free AAA and insulin in solution, helpful to recognize the microscopic details of AAA governed biological processes in living organisms.

scholarly journals Revealing Unknown Protein Structures Using Computational Conformational Sampling Guided by Experimental Hydrogen-Exchange Data

2018 ◽  
Vol 19 (11) ◽  
pp. 3406
Author(s):  
Didier Devaurs ◽  
Dinler Antunes ◽  
Lydia Kavraki
Keyword(s):  
Protein Structure ◽  
Computational Methods ◽  
Hydrogen Exchange ◽  
Protein Structures ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Computational Framework ◽  
Large Proteins ◽  
Unknown Protein ◽  
Exchange Data

Both experimental and computational methods are available to gather information about a protein’s conformational space and interpret changes in protein structure. However, experimentally observing and computationally modeling large proteins remain critical challenges for structural biology. Our work aims at addressing these challenges by combining computational and experimental techniques relying on each other to overcome their respective limitations. Indeed, despite its advantages, an experimental technique such as hydrogen-exchange monitoring cannot produce structural models because of its low resolution. Additionally, the computational methods that can generate such models suffer from the curse of dimensionality when applied to large proteins. Adopting a common solution to this issue, we have recently proposed a framework in which our computational method for protein conformational sampling is biased by experimental hydrogen-exchange data. In this paper, we present our latest application of this computational framework: generating an atomic-resolution structural model for an unknown protein state. For that, starting from an available protein structure, we explore the conformational space of this protein, using hydrogen-exchange data on this unknown state as a guide. We have successfully used our computational framework to generate models for three proteins of increasing size, the biggest one undergoing large-scale conformational changes.

scholarly journals Implicit modeling of the impact of adsorption on solid surfaces for protein mechanics and activity with a coarse-grain representation

2020 ◽  
Author(s):  
Nicolas Bourassin ◽  
Marc Baaden ◽  
Elisabeth Lojou ◽  
Sophie Sacquin-Mora
Keyword(s):  
Brownian Dynamics ◽  
Immobilized Enzymes ◽  
Protein Mechanics ◽  
Local Flexibility ◽  
Implicit Modeling ◽  
Dynamics And Function ◽  
Dynamics Simulations ◽  
And Function ◽  
Brownian Dynamics Simulations ◽  
The Impact

AbstractSurface immobilized enzymes play a key role in numerous biotechnological applications such as biosensors, biofuel cells or biocatalytic synthesis. As a consequence, the impact of adsorption on the enzyme structure, dynamics and function needs to be understood on the molecular level as it is critical for the improvement of these technologies. With this perspective in mind, we used a theoretical approach for investigating protein local flexibility on the residue scale that couples a simplified protein representation with an elastic network and Brownian Dynamics simulations. The protein adsorption on a solid surface is implicitly modeled via additional external constraints between the residues in contact with the surface. We first performed calculations on a redox enzyme, bilirubin oxidase (BOD) from M. verrucaria, to study the impact of adsorption on its mechanical properties. The resulting rigidity profiles show that, in agreement with the available experimental data, the mechanical variations observed in the adsorbed BOD will depend on its orientation and its anchor residues (i.e. residues that are in contact with the functionalized surface). Additional calculations on ribonuclease A and nitroreductase shed light on how seemingly stable adsorbed enzymes can nonetheless display an important decrease in their catalytic activity resulting from a perturbation of their mechanics and internal dynamics.

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