Mrinmoy Mukherjee - Academia.edu (original) (raw)
Uploads
Papers by Mrinmoy Mukherjee
The Journal of Physical Chemistry B, 2020
The molecular mechanism of osmolytes on the stabilization of native states of protein is still co... more The molecular mechanism of osmolytes on the stabilization of native states of protein is still controversial irrespective of extensive studies over several decades. Recent investigations in terms of experiments and molecular dynamics simulations challenge the popular osmophobic model explaining the mechanistic action of protein-stabilizing osmolytes. The current Perspective presents an updated view on the mechanistic action of osmolytes in light of resurgence of interesting experiments and computer simulations over the past few years in this direction. In this regard, the Perspective adopts a bottom-up approach starting from hydrophobic interactions and eventually adds complexity in the system, going toward the protein, in a complex topology of hydrophobic and electrostatic interactions. Finally, the Perspective unifies osmolyte-induced protein conformational equilibria in terms of preferential interaction theory, irrespective of individual preferential binding or exclusion of osmolytes depending on different osmolytes and protein surfaces. The Perspective also identifies future research directions that can potentially shape this interesting area.
The Journal of Physical Chemistry B, 2020
The mechanism of protein stabilization by zwitterionic osmolytes has remained a long-standing puz... more The mechanism of protein stabilization by zwitterionic osmolytes has remained a long-standing puzzle. While osmolytes are prevalently hypothesized to stabilize proteins by preferentially excluding themselves from the protein surface, emerging experimental and theoretical lines of evidence of preferential binding of the popular osmolyte trimethyl amine Noxide (TMAO) to some protein surfaces are contradicting this view. Here, we address these contrasting perspectives by investigating the folding mechanism of a set of mini proteins in aqueous solutions of two different osmolytes glycine and TMAO via free energy simulations. Our results demonstrate that, while both osmolytes are found to stabilize the folded conformation of the mini proteins, their mechanisms of action can be mutually opposite: Specifically, glycine always depletes from the surface of all mini proteins, thereby conforming to the osmophobic model, but TMAO is found to display ambivalent signatures of protein-specific preferential binding to and exclusion from the protein surface. At the molecular level, the presence of an extended hydrophobic patch in protein topology is found to be a recurrent motif in proteins leading to favorable binding with TMAO. Finally, an analysis combining the preferential interaction theory and folding free energetics reveals that irrespective of preferential binding vs exclusion of osmolytes, it is the relative preferential depletion of osmolytes on transition from folded to unfolded conformations of proteins, which drives the overall conformational equilibrium toward the folded state in the presence of osmolytes. Taken together, moving beyond the model system and hypothesis, this work brings out contrasting mechanisms of stabilizing osmolytes on proteins and provides a unifying justification.
The Journal of Chemical Physics, 2019
Understanding the effect of glassy dynamics on the stability of bio-macromolecules and investigat... more Understanding the effect of glassy dynamics on the stability of bio-macromolecules and investigating the underlying relaxation processes governing degradation processes of these macromolecules are of immense importance in the context of bio-preservation. In this work we have studied the stability of a model polymer chain in a supercooled glass-forming liquid at different amount of supercooling in order to understand how dynamics of supercooled liquids influence the collapse behavior of the polymer. Our systematic computer simulation studies find that apart from long time relaxation processes (α relaxation), short time dynamics of the supercooled liquid, known as β relaxation plays an important role in controlling the stability of the model polymer. This is in agreement with some recent experimental findings. These observations are in stark contrast with the common belief that only long time relaxation processes are the sole player. We find convincing evidence that suggest that one might need to review the the vitrification hypothesis which postulates that α relaxations control the dynamics of biomolecules and thus α-relaxation time should be considered for choosing appropriate bio-preservatives. We hope that our results will lead to understand the primary factors in protein stabilization in the context of bio-preservation.
The mechanism of protein stabilization by zwiterionic osmolytes has remained a long-standing puzz... more The mechanism of protein stabilization by zwiterionic osmolytes has remained a long-standing puzzle. While the prevalent mechanistic hypothesis suggests an ‘osmo-phobic’ model in which osmolytes are assumed to stabilize proteins by preferentially excluding themselves from the protein surface, emerging evidences of preferential binding of popular osmolyte trimethyl amine N-oxide (TMAO) with hydrophobic macromolecules contradict this view. Here we address these contrasting perspectives by investigating the folding mechanism of a set of mini proteins in aqueous solutions of two different osmolytes glycine and TMAO, via free energy simulations. Our results demonstrate that, while both osmolytes are found to stabilize the folded conformation of the mini proteins, their mechanism of actions are mutually diverse: Specifically, glycine always depletes from the surface of all mini proteins, thereby conforming to the osmophobic model; but TMAO is found to display ambivalent signatures of prot...
The Journal of Physical Chemistry B, 2019
Cells survive in extreme environmental conditions by accumulating small organic molecules called ... more Cells survive in extreme environmental conditions by accumulating small organic molecules called osmolytes. While we have reached a consensus on the role of osmolytes towards macromolecular conformational stability at a single-macromolecule level, there is a lack of clarity on how osmolytes might influence macromolecular aggregation, an important feature to maintain cellular homeostasis. In this regard, here we explore how a popular osmolyte trimethyl amine N-oxide (TMAO) individually dictates the self-assembling propensity of hydrophobic and charged macromolecules. Our computer simulation based results reveal that the TMAO-induced self-aggregation of hydrophobic macromolecules, relative to that in neat water, is strongly dependent on macromolecular length-scale. Specifically, a free energy-based analysis indicates that the self-aggregation propensity of hydrophobic macromolecules in aqueous TMAO relative to neat water follows a non-monotonic trend: When compared with neat water, TMAO promotes hydrophobic self-assembly at a shorter length scale while discourages hydrophobic self-assembly at a larger length-scale. The overall non-monotonic trend is found to be entropy driven. A molecular-level analysis suggests that length scale-dependent preferential exclusion/binding of osmolytes
The Journal of Physical Chemistry B, 2019
Recent surge of investigations on osmolyte-induced conformational landscape of hydrophobic macrom... more Recent surge of investigations on osmolyte-induced conformational landscape of hydrophobic macromolecules notwithstanding, there is a lack of understanding of how the presence of coulombic charges in the macromolecule dictates its own conformational preference in aqueous media of osmolyte. Towards this end, in this work, we have computationally simulated the trimethyl amine N-oxide (TMAO)-induced collapse behaviour of a charge-neutral polymer by varying the number of oppositely signed charged monomeric beads of a given charge-density. From our free energy based analysis, at low charge-density, there emerges a non-monotonic trend in the extent of osmolyte-induced protection of collapsed conformation of the charge-neutral polymer as a function of number of periodically distributed charged monomers : Specifically, we observe that, at low charge density, with incremental introduction of oppositely charged monomers in the charge-neutral polymer, the process of osmolyte-induced polymer-collapse first gets free-energetically destabilised relative to that in uncharged polymer. However, with further increase in the number of charged monomers of low charge density, there is a recurrence of osmolyte-induced stabilisation of polymer collapse. On the contrary, the non-monotonic trend in osmolyte-induced polymer collapse across number 1
The Journal of Physical Chemistry B, 2018
Osmolytes' mechanism of protecting proteins against denaturation is a longstanding puzzle, furthe... more Osmolytes' mechanism of protecting proteins against denaturation is a longstanding puzzle, further complicated by the complex diversities inherent in protein sequences. An emergent approach in understanding osmolytes' mechanism of action towards biopolymer has been to investigate osmolytes' interplay with hydrophobic interaction, the major driving force of protein folding. However, the crucial question is whether all these protein-stabilizing osmolytes display a single unified mechanism towards hydrophobic interactions. By simulating the hydrophobic collapse of a macromolecule in aqueous solutions of two such osmoprotectants, Glycine and Trimethyl N-oxide (TMAO), both of which are known to stabilize protein's folded conformation, we here demonstrate that these two osmolytes can impart mutually contrasting effects towards hydrophobic interaction. While TMAO preserves its protectant nature across diverse range of polymer-osmolyte interactions, glycine is found to display an interesting cross-over from being a protectant at weaker polymer-osmolyte interaction to a denaturant of hydrophobicity at stronger polymer-osmolyte interactions. A preferential-interaction analysis reveals that a subtle balance of conformation-dependent exclusion/binding of
The Journal of Physical Chemistry B, 2020
The molecular mechanism of osmolytes on the stabilization of native states of protein is still co... more The molecular mechanism of osmolytes on the stabilization of native states of protein is still controversial irrespective of extensive studies over several decades. Recent investigations in terms of experiments and molecular dynamics simulations challenge the popular osmophobic model explaining the mechanistic action of protein-stabilizing osmolytes. The current Perspective presents an updated view on the mechanistic action of osmolytes in light of resurgence of interesting experiments and computer simulations over the past few years in this direction. In this regard, the Perspective adopts a bottom-up approach starting from hydrophobic interactions and eventually adds complexity in the system, going toward the protein, in a complex topology of hydrophobic and electrostatic interactions. Finally, the Perspective unifies osmolyte-induced protein conformational equilibria in terms of preferential interaction theory, irrespective of individual preferential binding or exclusion of osmolytes depending on different osmolytes and protein surfaces. The Perspective also identifies future research directions that can potentially shape this interesting area.
The Journal of Physical Chemistry B, 2020
The mechanism of protein stabilization by zwitterionic osmolytes has remained a long-standing puz... more The mechanism of protein stabilization by zwitterionic osmolytes has remained a long-standing puzzle. While osmolytes are prevalently hypothesized to stabilize proteins by preferentially excluding themselves from the protein surface, emerging experimental and theoretical lines of evidence of preferential binding of the popular osmolyte trimethyl amine Noxide (TMAO) to some protein surfaces are contradicting this view. Here, we address these contrasting perspectives by investigating the folding mechanism of a set of mini proteins in aqueous solutions of two different osmolytes glycine and TMAO via free energy simulations. Our results demonstrate that, while both osmolytes are found to stabilize the folded conformation of the mini proteins, their mechanisms of action can be mutually opposite: Specifically, glycine always depletes from the surface of all mini proteins, thereby conforming to the osmophobic model, but TMAO is found to display ambivalent signatures of protein-specific preferential binding to and exclusion from the protein surface. At the molecular level, the presence of an extended hydrophobic patch in protein topology is found to be a recurrent motif in proteins leading to favorable binding with TMAO. Finally, an analysis combining the preferential interaction theory and folding free energetics reveals that irrespective of preferential binding vs exclusion of osmolytes, it is the relative preferential depletion of osmolytes on transition from folded to unfolded conformations of proteins, which drives the overall conformational equilibrium toward the folded state in the presence of osmolytes. Taken together, moving beyond the model system and hypothesis, this work brings out contrasting mechanisms of stabilizing osmolytes on proteins and provides a unifying justification.
The Journal of Chemical Physics, 2019
Understanding the effect of glassy dynamics on the stability of bio-macromolecules and investigat... more Understanding the effect of glassy dynamics on the stability of bio-macromolecules and investigating the underlying relaxation processes governing degradation processes of these macromolecules are of immense importance in the context of bio-preservation. In this work we have studied the stability of a model polymer chain in a supercooled glass-forming liquid at different amount of supercooling in order to understand how dynamics of supercooled liquids influence the collapse behavior of the polymer. Our systematic computer simulation studies find that apart from long time relaxation processes (α relaxation), short time dynamics of the supercooled liquid, known as β relaxation plays an important role in controlling the stability of the model polymer. This is in agreement with some recent experimental findings. These observations are in stark contrast with the common belief that only long time relaxation processes are the sole player. We find convincing evidence that suggest that one might need to review the the vitrification hypothesis which postulates that α relaxations control the dynamics of biomolecules and thus α-relaxation time should be considered for choosing appropriate bio-preservatives. We hope that our results will lead to understand the primary factors in protein stabilization in the context of bio-preservation.
The mechanism of protein stabilization by zwiterionic osmolytes has remained a long-standing puzz... more The mechanism of protein stabilization by zwiterionic osmolytes has remained a long-standing puzzle. While the prevalent mechanistic hypothesis suggests an ‘osmo-phobic’ model in which osmolytes are assumed to stabilize proteins by preferentially excluding themselves from the protein surface, emerging evidences of preferential binding of popular osmolyte trimethyl amine N-oxide (TMAO) with hydrophobic macromolecules contradict this view. Here we address these contrasting perspectives by investigating the folding mechanism of a set of mini proteins in aqueous solutions of two different osmolytes glycine and TMAO, via free energy simulations. Our results demonstrate that, while both osmolytes are found to stabilize the folded conformation of the mini proteins, their mechanism of actions are mutually diverse: Specifically, glycine always depletes from the surface of all mini proteins, thereby conforming to the osmophobic model; but TMAO is found to display ambivalent signatures of prot...
The Journal of Physical Chemistry B, 2019
Cells survive in extreme environmental conditions by accumulating small organic molecules called ... more Cells survive in extreme environmental conditions by accumulating small organic molecules called osmolytes. While we have reached a consensus on the role of osmolytes towards macromolecular conformational stability at a single-macromolecule level, there is a lack of clarity on how osmolytes might influence macromolecular aggregation, an important feature to maintain cellular homeostasis. In this regard, here we explore how a popular osmolyte trimethyl amine N-oxide (TMAO) individually dictates the self-assembling propensity of hydrophobic and charged macromolecules. Our computer simulation based results reveal that the TMAO-induced self-aggregation of hydrophobic macromolecules, relative to that in neat water, is strongly dependent on macromolecular length-scale. Specifically, a free energy-based analysis indicates that the self-aggregation propensity of hydrophobic macromolecules in aqueous TMAO relative to neat water follows a non-monotonic trend: When compared with neat water, TMAO promotes hydrophobic self-assembly at a shorter length scale while discourages hydrophobic self-assembly at a larger length-scale. The overall non-monotonic trend is found to be entropy driven. A molecular-level analysis suggests that length scale-dependent preferential exclusion/binding of osmolytes
The Journal of Physical Chemistry B, 2019
Recent surge of investigations on osmolyte-induced conformational landscape of hydrophobic macrom... more Recent surge of investigations on osmolyte-induced conformational landscape of hydrophobic macromolecules notwithstanding, there is a lack of understanding of how the presence of coulombic charges in the macromolecule dictates its own conformational preference in aqueous media of osmolyte. Towards this end, in this work, we have computationally simulated the trimethyl amine N-oxide (TMAO)-induced collapse behaviour of a charge-neutral polymer by varying the number of oppositely signed charged monomeric beads of a given charge-density. From our free energy based analysis, at low charge-density, there emerges a non-monotonic trend in the extent of osmolyte-induced protection of collapsed conformation of the charge-neutral polymer as a function of number of periodically distributed charged monomers : Specifically, we observe that, at low charge density, with incremental introduction of oppositely charged monomers in the charge-neutral polymer, the process of osmolyte-induced polymer-collapse first gets free-energetically destabilised relative to that in uncharged polymer. However, with further increase in the number of charged monomers of low charge density, there is a recurrence of osmolyte-induced stabilisation of polymer collapse. On the contrary, the non-monotonic trend in osmolyte-induced polymer collapse across number 1
The Journal of Physical Chemistry B, 2018
Osmolytes' mechanism of protecting proteins against denaturation is a longstanding puzzle, furthe... more Osmolytes' mechanism of protecting proteins against denaturation is a longstanding puzzle, further complicated by the complex diversities inherent in protein sequences. An emergent approach in understanding osmolytes' mechanism of action towards biopolymer has been to investigate osmolytes' interplay with hydrophobic interaction, the major driving force of protein folding. However, the crucial question is whether all these protein-stabilizing osmolytes display a single unified mechanism towards hydrophobic interactions. By simulating the hydrophobic collapse of a macromolecule in aqueous solutions of two such osmoprotectants, Glycine and Trimethyl N-oxide (TMAO), both of which are known to stabilize protein's folded conformation, we here demonstrate that these two osmolytes can impart mutually contrasting effects towards hydrophobic interaction. While TMAO preserves its protectant nature across diverse range of polymer-osmolyte interactions, glycine is found to display an interesting cross-over from being a protectant at weaker polymer-osmolyte interaction to a denaturant of hydrophobicity at stronger polymer-osmolyte interactions. A preferential-interaction analysis reveals that a subtle balance of conformation-dependent exclusion/binding of