scholarly journals Why a diaminopyrrolic tripodal receptor binds mannosides in acetonitrile but not in water?

2014 ◽  
Vol 10 ◽  
pp. 1513-1523 ◽  
Author(s):  
Diogo Vila-Viçosa ◽  
Oscar Francesconi ◽  
Miguel Machuqueiro
Keyword(s):  
Molecular Dynamics ◽  
Conformational Space ◽  
Biological Processes ◽  
Synthetic Receptor ◽  
Constant Ph ◽  
Tripodal Receptor ◽  
Bond Network ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics ◽  
Dynamics Method

Intermolecular interactions involving carbohydrates and their natural receptors play important roles in several biological processes. The development of synthetic receptors is very useful to study these recognition processes. Recently, it was synthetized a diaminopyrrolic tripodal receptor that is selective for mannosides, which are obtained from mannose, a sugar with significant relevance in living systems. However, this receptor is significantly more active in acetonitrile than in water. In this work, we performed several molecular dynamics and constant-pH molecular dynamics simulations in acetonitrile and water to evaluate the conformational space of the receptor and to understand the molecular detail of the receptor–mannoside interaction. The protonation states sampled by the receptor show that the positive charges are always as distant as possible in order to avoid large intramolecular repulsions. Moreover, the conformational space of the receptor is very similar in water above pH 4.0 and in acetonitrile. From the simulations with the mannoside, we observe that the interactions are more specific in acetonitrile (mainly hydrogen bonds) than in water (mainly hydrophobic). Our results suggest that the readiness of the receptor to bind mannoside is not significantly affected in water (above pH 4.0). Probably, the hydrogen bond network that is formed in acetonitrile (which is weaker in water) is the main reason for the higher activity in this solvent. This work also presents a new implementation of the stochastic titration constant-pH molecular dynamics method to a synthetic receptor of sugars and attests its ability to describe the protonation/conformation coupling in these molecules.

scholarly journals Continuous constant pH Molecular Dynamics Simulations of Transmembrane Proteins

2020 ◽  
Author(s):  
Yandong Huang ◽  
Jack A. Henderson ◽  
Jana Shen
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Dynamics ◽  
Transmembrane Proteins ◽  
Proton Channels ◽  
Proton Coupling ◽  
Constant Ph ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics ◽  
Dynamics Method

AbstractMany membrane channels, transporters, and receptors utilize a pH gradient or proton coupling to drive functionally relevant conformational transitions. Conventional molecular dynamics simulations employ fixed protonation states, thus neglecting the coupling between protonation and conformational equilibria. Here we describe the membrane-enabled hybrid-solvent continuous constant pH molecular dynamics method for capturing atomic details of proton-coupled conformational dynamics of transmembrane proteins. Example protocols from our recent application studies of proton channels and ion/substrate transporters are discussed.

scholarly journals On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 99
Author(s):  
Cristian Privat ◽  
Sergio Madurga ◽  
Francesc Mas ◽  
Jaime Rubio-Martínez
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Md Simulations ◽  
Point Of View ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Protonation State ◽  
Constant Ph ◽  
Biochemical Systems ◽  
Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

scholarly journals pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL

2018 ◽  
Vol 20 (5) ◽  
pp. 3523-3530 ◽  
Author(s):  
Zhi Yue ◽  
Jana Shen
Keyword(s):  
Molecular Dynamics ◽  
Energy Barrier ◽  
Molten Globule ◽  
Free Energy Barrier ◽  
Molten Globule State ◽  
Constant Ph ◽  
Ph Dependent ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics ◽  
Folding Free Energy

Constant pH molecular dynamics simulations of BBL reveals negligible folding free energy barrier that is pH dependent and a sparsely populated dry molten globule state.

scholarly journals Probing the Accuracy of Explicit Solvent Constant pH Molecular Dynamics Simulations for Peptides

2020 ◽  
Vol 16 (4) ◽  
pp. 2561-2569 ◽  
Author(s):  
Plamen Dobrev ◽  
Sahithya Phani Babu Vemulapalli ◽  
Nilamoni Nath ◽  
Christian Griesinger ◽  
Helmut Grubmüller
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Constant Ph ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics

scholarly journals Probing the Accuracy of Explicit Solvent Constant pH Molecular Dynamics Simulations for Peptides

2020 ◽  
Vol 118 (3) ◽  
pp. 140a
Author(s):  
Plamen N. Dobrev ◽  
Sahithya Vemulapalli ◽  
Nilamoni Nath ◽  
Christian Griesinger ◽  
Helmut Grubmueller
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Constant Ph ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics

scholarly journals GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pKa Predictions with Single-pH Simulations

2019 ◽  
Author(s):  
Robert C. Harris ◽  
Jana Shen ◽  
Yandong Huang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Method ◽  
Generalized Born ◽  
Constant Ph ◽  
Testing Data ◽  
Constant Ph Molecular Dynamics ◽  
Dynamics Method

This paper reports a GPU-accelerated implementation and testing data of the generalized Born based continuous constant pH molecular dynamics method in the Amber package.

scholarly journals Charge Interactions in a Highly Charge-depleted Protein

2020 ◽  
Author(s):  
Stefan Hervø-Hansen ◽  
Casper Højgaard ◽  
Kristoffer Enøe Johansson ◽  
Yong Wang ◽  
Khadija Wahni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Nmr Spectroscopy ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Protein Electrostatics ◽  
Surface Charges ◽  
Constant Ph ◽  
Charged Residues ◽  
Dynamics Simulations ◽  
Constant Ph Molecular Dynamics

ABSTRACTInteractions between charged residues are difficult to study because of the complex network of interactions found in most proteins. We have designed a purposely simple system to investigate this problem by systematically introducing individual and pairs of charged and titratable residues in a protein otherwise free of such residues. We used constant pH molecular dynamics simulations, NMR spectroscopy, and thermodynamic double mutant cycles to probe the structure and energetics of the interaction between the charged residues. We found that the partial burial of surface charges contributes to a shift in pKa value, causing an aspartate to titrate in the neutral pH range. Additionally, the interaction between pairs of residues was found to be highly context dependent, with some pairs having no apparent preferential interaction, while other pairs would engage in coupled titration forming a highly stabilized salt bridge. We find good agreement between experiments and simulations, and use the simulations to rationalize our observations and to provide a detailed mechanistic understanding of the electrostatic interactions.SignificanceElectrostatic forces are important for protein folding and are favored targets of protein engineering. However, despite the many advances in the field of protein electrostatics, the prediction of changes in protein structure and function upon introduction or removal of titratable residues is still complicated. In order to provide a basic understanding of protein electrostatics we here characterize a highly charge-depleted protein and its titratable variants by a combination of NMR spectroscopy and constant pH molecular dynamics simulations. Our investigations reveal how strongly interacting residues engaged in salt bridging, can be characterized. Furthermore, our study may also enrich and facilitate the understanding of dehydration of salt-bridges and its potential effect on protein stability.

scholarly journals Unravelling Constant pH Molecular Dynamics in Oligopeptides with Explicit Solvation Model

Polymers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 3311
Author(s):  
Cristian Privat ◽  
Sergio Madurga ◽  
Francesc Mas ◽  
Jaime Rubio-Martinez
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Protonation State ◽  
Solvation Model ◽  
Great Ability ◽  
Constant Ph ◽  
Constant Ph Molecular Dynamics ◽  
Explicit Solvation

An accurate description of the protonation state of amino acids is essential to correctly simulate the conformational space and the mechanisms of action of proteins or other biochemical systems. The pH and the electrochemical environments are decisive factors to define the effective pKa of amino acids and, therefore, the protonation state. However, they are poorly considered in Molecular Dynamics (MD) simulations. To deal with this problem, constant pH Molecular Dynamics (cpHMD) methods have been developed in recent decades, demonstrating a great ability to consider the effective pKa of amino acids within complex structures. Nonetheless, there are very few studies that assess the effect of these approaches in the conformational sampling. In a previous work of our research group, we detected strengths and weaknesses of the discrete cpHMD method implemented in AMBER when simulating capped tripeptides in implicit solvent. Now, we progressed this assessment by including explicit solvation in these peptides. To analyze more in depth the scope of the reported limitations, we also carried out simulations of oligopeptides with distinct positions of the titratable amino acids. Our study showed that the explicit solvation model does not improve the previously noted weaknesses and, furthermore, the separation of the titratable amino acids in oligopeptides can minimize them, thus providing guidelines to improve the conformational sampling in the cpHMD simulations.

Sign in / Sign up

Export Citation Format

Share Document