Modulation of the Conformational Dynamics of Apo-Adenylate Kinase through a π–Cation Interaction

Halder, Ritaban; Manna, Rabindra Nath; Chakraborty, Sandipan; Jana, Biman

doi:10.1021/acs.jpcb.7b01736

Cited by 15 publications

(13 citation statements)

References 66 publications

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“…Since folding/unfolding of a protein is a long time scale process, free energy simulations are generally preferred to explore the conformational landscape of protein. [96][97][98][99] During unfolding of a protein, the hydrophobic contacts which were present in the native state of the protein, disrupts. As a consequence of this, one often encounters structural changes in protein.…”

Section: Free Energy Landscape Of Hp-36 In Water and In Water-ethanol...mentioning

confidence: 99%

Exploring the role of hydrophilic amino acids in unfolding of protein in aqueous ethanol solution

Halder

Jana

2020

Proteins

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Hydrophobic association is the key contributor behind the formation of well packed core of a protein which is often believed to be an important step for folding from an unfolded chain to its compact functional form. While most of the protein folding/ unfolding studies have evaluated the changes in the hydrophobic interactions during chemical denaturation, the role of hydrophilic amino acids in such processes are not discussed in detail. Here we report the role of the hydrophilic amino acids behind ethanol induced unfolding of protein. Using free energy simulations, we show that chicken villin head piece (HP-36) protein unfolds gradually in presence of waterethanol binary mixture with increasing composition of ethanol. However, upon mutation of hydrophilic amino acids by glycine while keeping the hydrophobic amino acids intact, the compact state of the protein is found to be stable at all compositions with gradual flattening of the free energy landscape upon increasing compositions. The local environment around the protein in terms of ethanol/water number significantly differs in wild type protein compared to the mutated protein. The calculated Wyman-Tanford preferential binding coefficient of ethanol for wild type protein reveals that a greater number of cosolutes (here ethanol) bind to the unfolded state compared to its folded state. However, no significant increase in binding coefficient of ethanol at the unfolded state is found for mutated protein. Local-bulk partition coefficient calculation also suggests similar scenarios. Our results reveal that the weakening of hydrophobic interactions in aqueous ethanol solution along with larger preferential binding of ethanol to the unfolded state mediated by hydrophilic amino acids combinedly helps unfolding of protein in aqueous ethanol solution.

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Section: Free Energy Landscape Of Hp-36 In Water and In Water-ethanol...mentioning

confidence: 99%

Exploring the role of hydrophilic amino acids in unfolding of protein in aqueous ethanol solution

Halder

Jana

2020

Proteins

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“…Previously, we have also shown that the cation−π interaction is crucial for the conformational transition of apo adenylate kinase . Such interactions are often found to play an anchoring role in lipid specific recognition of membrane proteins .…”

Section: Resultsmentioning

confidence: 99%

“…54 Previously, we have also shown that the cation−π interaction is crucial for the conformational transition of apo adenylate kinase. 55 Such interactions are often found to play an anchoring role in lipid specific recognition of membrane proteins. 56 In cation−π interactions, the π-electron cloud interacts with the cationic part inside the same molecule or different molecules.…”

Section: Resultsmentioning

confidence: 99%

Exploring and Engineering the Conformational Landscape of Calmodulin through Specific Interactions

Halder

Jana

2019

J. Phys. Chem. B

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Conformational fluctuations often play paramount role in the function and activity of proteins. Calmodulin (CaM) is a calcium sensing protein that shows significant conformational flexibility on going from a ligand-free open state to a ligand-bound closed state. By employing large-scale equilibrium molecular dynamics simulations and free energy calculations, we have shown that apo CaM frequently visits a state that is neither fully open nor fully closed and referred to as half-open half-closed (HOHC) state. Such states are functionally relevant as they structurally resemble a ligand-bound closed state. Here, we have envisaged that the inherent conformational dynamics of CaM is primarily triggered by a dual salt bridge interaction between the glutamates and lysine at two different domains (N- and C-terminal domains) of the protein. Upon abolition of the dual salt bridge interaction, conformational dynamics is restricted and centered only near the open state. When a cation−π interaction is introduced while replacing the dual salt bridge interaction, the HOHC state tends to reappear as a stable state. Since salt bridge and cation−π interactions are frequently encountered in the protein dynasty, our work may illuminate an interesting direction toward controlling the conformational landscape of proteins through the modulation of minimal specific interactions.

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“…Finally, LYS57 is on the external part of NMP and has been identified to play a pivotal role in collaboration with ARG88 to block the release of adenine from the hydrophobic pocket of the protein . More generally, this amino acid is crucial for stabilizing the closed conformation of the kinase, , which was never observed throughout the simulation. The overall probability pattern persists as N increases, even though it is less pronounced.…”

Section: Resultsmentioning

confidence: 99%

An Information-Theory-Based Approach for Optimal Model Reduction of Biomolecules

Giulini

Menichetti

Shell

et al. 2020

J. Chem. Theory Comput.

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In theoretical modeling of a physical system, a crucial step consists of the identification of those degrees of freedom that enable a synthetic yet informative representation of it. While in some cases this selection can be carried out on the basis of intuition and experience, straightforward discrimination of the important features from the negligible ones is difficult for many complex systems, most notably heteropolymers and large biomolecules. We here present a thermodynamics-based theoretical framework to gauge the effectiveness of a given simplified representation by measuring its information content. We employ this method to identify those reduced descriptions of proteins, in terms of a subset of their atoms, that retain the largest amount of information from the original model; we show that these highly informative representations share common features that are intrinsically related to the biological properties of the proteins under examination, thereby establishing a bridge between protein structure, energetics, and function.

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Modulation of the Conformational Dynamics of Apo-Adenylate Kinase through a π–Cation Interaction

Cited by 15 publications

References 66 publications

Exploring the role of hydrophilic amino acids in unfolding of protein in aqueous ethanol solution

Exploring the role of hydrophilic amino acids in unfolding of protein in aqueous ethanol solution

Exploring and Engineering the Conformational Landscape of Calmodulin through Specific Interactions

An Information-Theory-Based Approach for Optimal Model Reduction of Biomolecules

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