scholarly journals Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

2019 ◽  
Author(s):  
Sophie Sacquin-Mora
Keyword(s):  
Experimental Data ◽  
Mechanical Properties ◽  
Small Molecules ◽  
Protein Function ◽  
Coarse Grain ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
New Approach ◽  
Conformational Ensembles ◽  
Dynamics Simulations

AbstractDynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein’s internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all atom classic molecular dynamics simulations and coarse grain calculations of the resulting conformational ensemble mechanical properties. Here we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy experiments are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.

scholarly journals Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

2019 ◽  
Vol 16 (156) ◽  
pp. 20190075
Author(s):  
Sophie Sacquin-Mora
Keyword(s):  
Experimental Data ◽  
Mechanical Properties ◽  
Small Molecules ◽  
Protein Function ◽  
Coarse Grain ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
New Approach ◽  
Conformational Ensembles ◽  
Dynamics Simulations

Dynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein's internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all-atom classic molecular dynamics simulations and coarse-grain calculations of the resulting conformational ensemble mechanical properties. Here, we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy experiments are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.

scholarly journals How to Determine Accurate Conformational Ensembles by Metadynamics Metainference: A Chignolin Study Case

2021 ◽  
Vol 8 ◽  
Author(s):  
Cristina Paissoni ◽  
Carlo Camilloni
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Experimental Information ◽  
Conformational Ensemble ◽  
Enhanced Sampling ◽  
Conformational Ensembles ◽  
Statistical Precision ◽  
Minimum Number ◽  
Study Case ◽  
Dynamics Simulations

The reliability and usefulness of molecular dynamics simulations of equilibrium processes rests on their statistical precision and their capability to generate conformational ensembles in agreement with available experimental knowledge. Metadynamics Metainference (M&M), coupling molecular dynamics with the enhanced sampling ability of Metadynamics and with the ability to integrate experimental information of Metainference, can in principle achieve both goals. Here we show that three different Metadynamics setups provide converged estimate of the populations of the three-states populated by a model peptide. Errors are estimated correctly by block averaging, but higher precision is obtained by performing independent replicates. One effect of Metadynamics is that of dramatically decreasing the number of effective frames resulting from the simulations and this is relevant for M&M where the number of replicas should be large enough to capture the conformational heterogeneity behind the experimental data. Our simulations allow also us to propose that monitoring the relative error associated with conformational averaging can help to determine the minimum number of replicas to be simulated in the context of M&M simulations. Altogether our data provides useful indication on how to generate sound conformational ensemble in agreement with experimental data.

scholarly journals The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

2021 ◽  
Vol 7 (17) ◽  
pp. eabf6106
Author(s):  
Weiwei He ◽  
Yen-Lin Chen ◽  
Lois Pollack ◽  
Serdal Kirmizialtin
Keyword(s):  
Structural Diversity ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
Dna And Rna ◽  
X Ray Scattering ◽  
Double Stranded Dna ◽  
Binding Partners ◽  
Rna Duplexes ◽  
Dynamics Simulations ◽  
Integrate Solution

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

scholarly journals The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Renata Fioravanti Tarabini ◽  
Luís Fernando Saraiva Macedo Timmers ◽  
Carlos Eduardo Sequeiros-Borja ◽  
Osmar Norberto de Souza
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Conformational Changes ◽  
Protein Function ◽  
Environmental Changes ◽  
Quaternary Structure ◽  
Single Point ◽  
Point Mutations ◽  
Conformational Ensembles ◽  
Dynamics Simulations ◽  
Coa Reductase

Abstract Flexibility is a feature intimately related to protein function, since conformational changes can be used to describe environmental changes, chemical modifications, protein-protein and protein-ligand interactions. In this study, we have investigated the influence of the quaternary structure of 2-trans-enoyl-ACP (CoA) reductase or InhA, from Mycobacterium tuberculosis, to its flexibility. We carried out classical molecular dynamics simulations using monomeric and tetrameric forms to elucidate the enzyme’s flexibility. Overall, we observed statistically significant differences between conformational ensembles of tertiary and quaternary structures. In addition, the enzyme’s binding site is the most affected region, reinforcing the importance of the quaternary structure to evaluate the binding affinity of small molecules, as well as the effect of single point mutations to InhA protein dynamics.

scholarly journals Mechanical variations in proteins with large-scale motions highlight the formation of structural locks

2017 ◽  
Author(s):  
Sophie Sacquin-Mora
Keyword(s):  
Mechanical Properties ◽  
Protein Function ◽  
Large Scale ◽  
Structural Changes ◽  
Coarse Grain ◽  
Local Rigidity ◽  
New Class ◽  
Closed Conformation ◽  
Closed Structure ◽  
The Impact

AbstractProtein function depends just as much on flexibility as on structure, and in numerous cases, a protein’s biological activity involves transitions that will impact both its conformation and its mechanical properties. Here, we use a coarse-grain approach to investigate the impact of structural changes on protein flexibility. More particularly, we focus our study on proteins presenting large-scale motions. We show how calculating directional force constants within residue pairs, and investigating their variation upon protein closure, can lead to the detection of a limited set of residues that form a structural lock in the protein’s closed conformation. This lock, which is composed of residues whose side-chains are tightly interacting, highlights a new class of residues that are important for protein function by stabilizing the closed structure, and that cannot be detected using earlier tools like local rigidity profiles or distance variations maps, or alternative bioinformatics approaches, such as coevolution scores.

Theoretical Interpretation of High-Performance Chromatographic Data for a Heterogeneous Series of Compounds

1992 ◽  
Vol 57 (1) ◽  
pp. 33-45
Author(s):  
Vladimír Jakuš
Keyword(s):  
Experimental Data ◽  
High Performance ◽  
Theoretical Interpretation ◽  
Retention Data ◽  
Theoretical Evaluation ◽  
New Approach ◽  
Free Energy Of Solvation ◽  
Rp Hplc ◽  
Mobile Phases ◽  
Reversed Phases

A new approach to theoretical evaluation of the Gibbs free energy of solvation was applied for estimation of retention data in high-performance liquid chromatography on reversed phases (RP-HPLC). Simple and improved models of stationary and mobile phases in RP-HPLC were employed. Statistically significant correlations between the calculated and experimental data were obtained for a heterogeneous series of twelve compounds.

IDENTIFICATION OF SELETIVE CLAUDIN CATION CHANNEL BLOCKERS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Jingjing Ma ◽  
Emma Wu ◽  
Ye Li ◽  
William Seibel ◽  
Le Shen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Binding Modes ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Dynamics Simulations ◽  
In Silico Models

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that compounds that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative small molecules that bind in the claudin-15 pore. AutoDock Vina was initially used to assess rigid docking using small compound databases. The small molecules were analyzed based on binding affinity to the pore and visualized using VMD for their potential blockage of the channel. Clusters of binding modes were identified based on the prominent interacting residues of the protein with the small molecules. We initially screened 10,500 compounds from within the UIC Centre for Drug Discovery and a cross-section of 10,000 compounds from the NCI open compound repository. This initial screen allowed us to identify 2 first-in-class selective claudin-15 blockers with efficacy in MDCK monolayers induced to express claudin-15 and in wildtype duodenum. Next, we screened the entire NCI open compound repository for additional molecules structurally related to our best initially identified molecule and this has allowed us to identify 13 additional molecules that increase TER of claudin-15 expressing MDCK monolayers by 90–160%. Additionally, these molecules possess similar structural components that will be collected in a fragment library and explored through molecular dynamics simulations. We also developed a claudin-2 homology model on which we are performing docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Our study will provide important insight into the role of claudin-dependent cation permeability in fundamental physiology, which we believe will lead to the utility of claudin blockers as a novel and much needed approach to treat diseases such as IBD.

scholarly journals An Additive Model to Predict the Rheological and Mechanical Properties of Polypropylene Blends Made by Virgin and Reprocessed Components

Recycling ◽  
2021 ◽  
Vol 6 (1) ◽  
pp. 2
Author(s):  
Francesco Paolo La Mantia ◽  
Maria Chiara Mistretta ◽  
Vincenzo Titone
Keyword(s):  
Experimental Data ◽  
Mechanical Properties ◽  
Additive Model ◽  
Industrial Process ◽  
Theoretical Predictions ◽  
Experimental Values ◽  
Polypropylene Blends ◽  
Polypropylene Sample

In this work, an additive model for the prediction of the rheological and mechanical properties of monopolymer blends made by virgin and reprocessed components is proposed. A polypropylene sample has been reprocessed more times in an extruder and monopolymer blends have been prepared by simulating an industrial process. The scraps are exposed to regrinding and are melt reprocessed before mixing with the virgin polymer. The reprocessed polymer is, then, subjected to some thermomechanical degradation. Rheological and mechanical experimental data have been compared with the theoretical predictions. The results obtained showed that the values of this simple additive model are a very good fit for the experimental values of both rheological and mechanical properties.

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