We carry out a linear elastic analysis to study wavy structure generation on lipid membrane by pe... more We carry out a linear elastic analysis to study wavy structure generation on lipid membrane by peripheral membrane proteins. We model the lipid membrane as linearly elastic and anisotropic material. The hydrophobic insertion by proteins into the lipid membrane has been idealized as penetration of rigid rod-like inclusions into the membrane and the electrostatic interaction between protein and membrane has been modeled by a distributed surface traction acting on the membrane surface. With the proposed model we study curvature generation by several binding domains of peripheral membrane proteins containing BAR domains and amphipathic alpha-helices. It is observed that electrostatic interaction is essential for curvature generation by the BAR domains.
Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition ... more Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition in vesicles.
We consider steady, fully-developed flows of deformable, inelastic grains driven by gravity betwe... more We consider steady, fully-developed flows of deformable, inelastic grains driven by gravity between identical bumpy walls. Using constitutive relations from extended kinetic theory (EKT) for the erodible bed near the centreline and the collisional flow between the surfaces of the bed and the walls, we calculate the fields of mean velocity, fluctuation velocity and solid volume fraction across the chute. We consider both situations in which the solid volume fraction at and near the centreline is high enough to form a bed and when it is not. We compare results predicted by EKT with recent discrete element simulations results, and obtain very good agreement.
Cellular membranes are highly dynamic in shape. They can rapidly and precisely regulate their sha... more Cellular membranes are highly dynamic in shape. They can rapidly and precisely regulate their shape to perform various cellular functions. The protein's ability to sense membrane curvature is essential in various biological events such as cell signaling and membrane trafficking. As they are bound, these curvature-sensing proteins may also change the local membrane shape by one or more curvature driving mechanisms. Established curvature-sensing/driving mechanisms rely on proteins with specific structural features such as amphipathic helices and intrinsically curved shapes. However, the recent discovery and characterization of many proteins have shattered the protein structure-function paradigm, believing that the protein functions require a unique structural feature. Typically, such structure-independent functions are carried either entirely by intrinsically disordered proteins or hybrid proteins containing disordered regions and structured domains. It is becoming more apparent that disordered proteins and regions can be potent sensors/inducers of membrane curvatures. In this article, we outline the basic features of disordered proteins and regions, the motifs in such proteins that encode the function, membrane remodeling by disordered proteins and regions, and assays that may be employed to investigate curvature sensing and generation by ordered/disordered proteins.
In this work, we study the adhesion of multi-component vesicle membrane to both flat and curved s... more In this work, we study the adhesion of multi-component vesicle membrane to both flat and curved substrates, based on the conventional Helfrich bending energy for multi-component vesicles and adhesion potentials of different forms. A phase field formulation is used to describe the different components of the vesicle. For the axisymmetric case, a number of representative equilibrium vesicle shapes are computed and some energy diagrams are presented which reveal the dependence of the calculated shapes and solution branches on various parameters including both bending moduli and spontaneous curvatures as well as the adhesion potential constants. Our computation also confirms a recent experimental observation that the adhesion effect may promote phase separation in twocomponent vesicle membranes.
Adsorption of proteins on membrane surfaces plays an important role in cell biological processes.... more Adsorption of proteins on membrane surfaces plays an important role in cell biological processes. In this work, we develop a two-dimensional fluid model for proteins. The protein molecules have been modeled as two-dimensional convex and soft particles. The Lennard-Jones potential for circular particles and Kihara (12,6) potential for elliptical particles with hard core have been used to model pairwise intermolecular interactions. The equation of state of the fluid model has been derived using Weeks-Chandler-Andersen decomposition and it involves three parameters, an attraction, a repulsion, and a size parameter, which depend on the shape and core size of the molecules. For validation of the model, a two-dimensional molecular dynamics simulation has been performed. Finally, the model has been applied to study the adsorption of proteins on a flat membrane. In comparison with the existing model of hard and convex particles for protein adsorption, our model predicts a higher packing fraction for the adsorption equilibria. Although the present work is based on Lennard-Jones-type interaction, it can be extended for other specific soft interactions between convex molecules. Thus the model has general applicability for any other two-dimensional adsorption systems of molecules with soft interaction.
Cell membrane proteins, both bound and integral, are known to preferentially accumulate at membra... more Cell membrane proteins, both bound and integral, are known to preferentially accumulate at membrane locations with curvatures favorable to their shape. This is mainly due to the curvature dependent interaction between membrane proteins and their lipid environment. Here, we analyze the effects of the protein-lipid bilayer interaction energy due to mismatch between the protein shape and the principal curvatures of the surrounding bilayer. The role of different macroscopic parameters that define the interaction energy term is elucidated in relation to recent experiment in which the lateral distribution of a membrane embedded protein potassium channel KvAP is measured on a giant unilamellar lipid vesicle (reservoir) and a narrow tubular extensiona tetherkept at constant length. The dependence of the sorting ratio, defined as the ratio between the areal density of the protein on the tether and on the vesicle, on the inverse tether radius is influenced by the strength of the interaction, the intrinsic shape of the membrane embedded protein, and its abundance in the reservoir. It is described how the values of these constants can be extracted from experiments. The intrinsic principal curvatures of a protein are related to the tether radius at which the sorting ratio attains its maximum value. The estimate of the principal intrinsic curvature of the protein KvAP, obtained by comparing the experimental and theoretical sorting behavior, is consistent with the available information on its structure.
The curvature sensitive localization of proteins on membranes is vital for many cell biological p... more The curvature sensitive localization of proteins on membranes is vital for many cell biological processes. Coarse-grained models are routinely employed to study the curvature sensing phenomena and membrane morphology at the length scale of few micrometers. Two prevalent phenomenological models exist for modeling experimental observations of curvature sensing, (1) the spontaneous curvature model and (2) the curvature mismatch model, which differ in their treatment of the change in elastic energy due to the binding of proteins on the membrane. In this work, the prediction of sensing and generation behaviour, by these two models, are investigated using analytical calculations as well as Dynamic Triangulation Monte Carlo simulations of quasi-spherical vesicles. While the spontaneous curvature model yields a monotonically decreasing sensing curve as a function of vesicle radius, the curvature mismatch model results in a non-monotonic sensing curve. We highlight the main differences in the interpretation of the protein-related parameters in the two models. We further propose that the spontaneous curvature model is appropriate for modeling peripheral proteins employing the hydrophobic insertion mechanism, with minimal modification of membrane rigidity, while the curvature mismatch model is appropriate for modeling curvature generation using scaffolding mechanism where there is significant stiffening of the membrane due to protein binding.
Membrane curvature of a biological cell is actively involved in various fundamental cell biologic... more Membrane curvature of a biological cell is actively involved in various fundamental cell biological functions. It has been discovered that membrane curvature and binding of peripheral membrane proteins follow a symbiotic relationship. The exact mechanism behind this interplay of protein binding and membrane curvature has not yet been properly understood. To elucidate the mechanism, we study curvature sorting of proteins in a model system of a tether pulled from a Giant Unilamellar Vesicle (GUV) using mechanical-thermodynamic models. The concentration of proteins bound to membrane changes significantly due to curvature. This has also been observed in experiments by other researchers. We also find that there is a phase transition based on protein concentration and we discuss coexistence of phases and stability of solutions. Furthermore, when sorting is favorable, the increase in protein concentration stabilizes the tether in the sense that less pulling force is required to maintain the tether. A similar mechanism may be in place, when motor proteins pull tethers from donor membranes.
We study steady, fully developed, axisymmetric flows of soft, inelastic grains within a vertical ... more We study steady, fully developed, axisymmetric flows of soft, inelastic grains within a vertical circular pipe under the influence of gravity. We use extended kinetic theory to describe the collisional flow and include a region above the critical solid volume fraction near the center line that is the analog of an erodible bed. We calculate the profiles of velocity, shear stress, granular temperature, and particle concentration across the pipe for a variety of volume flow rates and pipe radii. We compare these with those measured in discrete element simulations by Barker et al. [J. Fluid Mech. 930, A21 (2022)] and see good agreement.
HAL (Le Centre pour la Communication Scientifique Directe), Nov 22, 2022
Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions rang... more Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions ranging from exocytosis to cell proliferation at different time scales. In the vasculature, a constant adenosine triphosphate (ATP) concentration is maintained because of ATP released by red blood cells (RBCs). These ATP molecules continuously react with purinergic receptors on the surface of endothelial cells (ECs). Consequently, a cascade of chemical reactions are triggered that result in a transient cytoplasmic calcium (Ca 2+), followed by return to its basal concentration. The mathematical models proposed in literature are able to reproduce the transient peak. However, the trailing concentration is always higher than the basal cytoplasmic Ca 2+ concentrations, and the Ca 2+ concentration in endoplasmic reticulum (ER) remains lower than its initial concentration. This means that the intracellular homeostasis is not recovered. We propose, herein, a minimal model of calcium kinetics. We find that the desensitization of EC surface receptors due to phosphorylation and recycling plays a vital role in maintaining calcium homeostasis in the presence of a constant stimulus (ATP). The model is able to capture several experimental observations such as refilling of Ca 2+ in the ER, variation of cytoplasmic Ca 2+ transient peak in ECs, the resting cytoplasmic Ca 2+ concentration, the effect of removing ATP from the plasma on Ca 2+ homeostasis, and the saturation of cytoplasmic Ca 2+ transient peak with increase in ATP concentration. Direct confrontation with several experimental results is conducted.This work paves the way to systematic studies for coupling between blood flow and chemical signaling, and should contribute to a better understanding of the relation between (patho)physiological conditions and Ca 2+ kinetics.
Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions rang... more Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions ranging from exocytosis to cell proliferation at different time scales. In the vasculature, a constant adenosine triphosphate (ATP) concentration is maintained because of ATP released by red blood cells (RBCs). These ATP molecules continuously react with purinergic receptors on the surface of endothelial cells (ECs). Consequently, a cascade of chemical reactions are triggered that result in a transient cytoplasmic calcium (Ca 2+), followed by return to its basal concentration. The mathematical models proposed in literature are able to reproduce the transient peak. However, the trailing concentration is always higher than the basal cytoplasmic Ca 2+ concentrations, and the Ca 2+ concentration in endoplasmic reticulum (ER) remains lower than its initial concentration. This means that the intracellular homeostasis is not recovered. We propose, herein, a minimal model of calcium kinetics. We find that the desensitization of EC surface receptors due to phosphorylation and recycling plays a vital role in maintaining calcium homeostasis in the presence of a constant stimulus (ATP). The model is able to capture several experimental observations such as refilling of Ca 2+ in the ER, variation of cytoplasmic Ca 2+ transient peak in ECs, the resting cytoplasmic Ca 2+ concentration, the effect of removing ATP from the plasma on Ca 2+ homeostasis, and the saturation of cytoplasmic Ca 2+ transient peak with increase in ATP concentration. Direct confrontation with several experimental results is conducted.This work paves the way to systematic studies for coupling between blood flow and chemical signaling, and should contribute to a better understanding of the relation between (patho)physiological conditions and Ca 2+ kinetics.
Theoretical modeling of curvature induced sorting of cell-membrane proteins including soft intera... more Theoretical modeling of curvature induced sorting of cell-membrane proteins including soft interaction potentials, shape anisotropy, and curvature anisotropy.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2021
BACKGROUND Membrane-bound intracellular organelles have characteristic shapes attributed to diffe... more BACKGROUND Membrane-bound intracellular organelles have characteristic shapes attributed to different local membrane curvatures, and these attributes are conserved across species. Over the past decade, it has been confirmed that specific proteins control the large curvatures of the membrane, whereas many others due to their specific structural features can sense the curvatures and bind to the specific geometrical cues. Elucidating the interplay between sensing and induction is indispensable to understand the mechanisms behind various biological processes such as vesicular trafficking and budding. SCOPE OF REVIEW We provide an overview of major classes of membrane proteins and the mechanisms of curvature sensing and induction. We then discuss the importance of membrane elastic characteristics to induce the membrane shapes similar to intracellular organelles. Finally, we survey recently available assays developed for studying the curvature sensing and induction by many proteins. MAJOR CONCLUSIONS Recent theoretical/computational modeling along with experimental studies have uncovered fascinating connections between lipid membrane and protein interactions. However, the phenomena of protein localization and synchronization to generate spatiotemporal dynamics in membrane morphology are yet to be fully understood. GENERAL SIGNIFICANCE The understanding of protein-membrane interactions is essential to shed light on various biological processes. This further enables the technological applications of many natural proteins/peptides in therapeutic treatments. The studies of membrane dynamic shapes help to understand the fundamental functions of membranes, while the medicinal roles of various macromolecules (such as proteins, peptides, etc.) are being increasingly investigated.
The curvature sensitive localization of proteins on membranes is vital for many cell biological p... more The curvature sensitive localization of proteins on membranes is vital for many cell biological processes. Coarse-grained models are routinely employed to study the curvature sensing phenomena and membrane morphology at the length scale of few micrometers. Two prevalent phenomenological models exist for modeling experimental observations of curvature sensing, (1) the spontaneous curvature model and (2) the curvature mismatch model, which differ in their treatment of the change in elastic energy due to the binding of proteins on the membrane. In this work, the prediction of sensing and generation behaviour, by these two models, are investigated using analytical calculations as well as Dynamic Triangulation Monte Carlo simulations of quasi-spherical vesicles. While the spontaneous curvature model yields a monotonically decreasing sensing curve as a function of vesicle radius, the curvature mismatch model results in a non-monotonic sensing curve. We highlight the main differences in the interpretation of the protein-related parameters in the two models. We further propose that the spontaneous curvature model is appropriate for modeling peripheral proteins employing the hydrophobic insertion mechanism, with minimal modification of membrane rigidity, while the curvature mismatch model is appropriate for modeling curvature generation using scaffolding mechanism where there is significant stiffening of the membrane due to protein binding.
Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition ... more Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition in vesicles.
We carry out a linear elastic analysis to study wavy structure generation on lipid membrane by pe... more We carry out a linear elastic analysis to study wavy structure generation on lipid membrane by peripheral membrane proteins. We model the lipid membrane as linearly elastic and anisotropic material. The hydrophobic insertion by proteins into the lipid membrane has been idealized as penetration of rigid rod-like inclusions into the membrane and the electrostatic interaction between protein and membrane has been modeled by a distributed surface traction acting on the membrane surface. With the proposed model we study curvature generation by several binding domains of peripheral membrane proteins containing BAR domains and amphipathic alpha-helices. It is observed that electrostatic interaction is essential for curvature generation by the BAR domains.
Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition ... more Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition in vesicles.
We consider steady, fully-developed flows of deformable, inelastic grains driven by gravity betwe... more We consider steady, fully-developed flows of deformable, inelastic grains driven by gravity between identical bumpy walls. Using constitutive relations from extended kinetic theory (EKT) for the erodible bed near the centreline and the collisional flow between the surfaces of the bed and the walls, we calculate the fields of mean velocity, fluctuation velocity and solid volume fraction across the chute. We consider both situations in which the solid volume fraction at and near the centreline is high enough to form a bed and when it is not. We compare results predicted by EKT with recent discrete element simulations results, and obtain very good agreement.
Cellular membranes are highly dynamic in shape. They can rapidly and precisely regulate their sha... more Cellular membranes are highly dynamic in shape. They can rapidly and precisely regulate their shape to perform various cellular functions. The protein's ability to sense membrane curvature is essential in various biological events such as cell signaling and membrane trafficking. As they are bound, these curvature-sensing proteins may also change the local membrane shape by one or more curvature driving mechanisms. Established curvature-sensing/driving mechanisms rely on proteins with specific structural features such as amphipathic helices and intrinsically curved shapes. However, the recent discovery and characterization of many proteins have shattered the protein structure-function paradigm, believing that the protein functions require a unique structural feature. Typically, such structure-independent functions are carried either entirely by intrinsically disordered proteins or hybrid proteins containing disordered regions and structured domains. It is becoming more apparent that disordered proteins and regions can be potent sensors/inducers of membrane curvatures. In this article, we outline the basic features of disordered proteins and regions, the motifs in such proteins that encode the function, membrane remodeling by disordered proteins and regions, and assays that may be employed to investigate curvature sensing and generation by ordered/disordered proteins.
In this work, we study the adhesion of multi-component vesicle membrane to both flat and curved s... more In this work, we study the adhesion of multi-component vesicle membrane to both flat and curved substrates, based on the conventional Helfrich bending energy for multi-component vesicles and adhesion potentials of different forms. A phase field formulation is used to describe the different components of the vesicle. For the axisymmetric case, a number of representative equilibrium vesicle shapes are computed and some energy diagrams are presented which reveal the dependence of the calculated shapes and solution branches on various parameters including both bending moduli and spontaneous curvatures as well as the adhesion potential constants. Our computation also confirms a recent experimental observation that the adhesion effect may promote phase separation in twocomponent vesicle membranes.
Adsorption of proteins on membrane surfaces plays an important role in cell biological processes.... more Adsorption of proteins on membrane surfaces plays an important role in cell biological processes. In this work, we develop a two-dimensional fluid model for proteins. The protein molecules have been modeled as two-dimensional convex and soft particles. The Lennard-Jones potential for circular particles and Kihara (12,6) potential for elliptical particles with hard core have been used to model pairwise intermolecular interactions. The equation of state of the fluid model has been derived using Weeks-Chandler-Andersen decomposition and it involves three parameters, an attraction, a repulsion, and a size parameter, which depend on the shape and core size of the molecules. For validation of the model, a two-dimensional molecular dynamics simulation has been performed. Finally, the model has been applied to study the adsorption of proteins on a flat membrane. In comparison with the existing model of hard and convex particles for protein adsorption, our model predicts a higher packing fraction for the adsorption equilibria. Although the present work is based on Lennard-Jones-type interaction, it can be extended for other specific soft interactions between convex molecules. Thus the model has general applicability for any other two-dimensional adsorption systems of molecules with soft interaction.
Cell membrane proteins, both bound and integral, are known to preferentially accumulate at membra... more Cell membrane proteins, both bound and integral, are known to preferentially accumulate at membrane locations with curvatures favorable to their shape. This is mainly due to the curvature dependent interaction between membrane proteins and their lipid environment. Here, we analyze the effects of the protein-lipid bilayer interaction energy due to mismatch between the protein shape and the principal curvatures of the surrounding bilayer. The role of different macroscopic parameters that define the interaction energy term is elucidated in relation to recent experiment in which the lateral distribution of a membrane embedded protein potassium channel KvAP is measured on a giant unilamellar lipid vesicle (reservoir) and a narrow tubular extensiona tetherkept at constant length. The dependence of the sorting ratio, defined as the ratio between the areal density of the protein on the tether and on the vesicle, on the inverse tether radius is influenced by the strength of the interaction, the intrinsic shape of the membrane embedded protein, and its abundance in the reservoir. It is described how the values of these constants can be extracted from experiments. The intrinsic principal curvatures of a protein are related to the tether radius at which the sorting ratio attains its maximum value. The estimate of the principal intrinsic curvature of the protein KvAP, obtained by comparing the experimental and theoretical sorting behavior, is consistent with the available information on its structure.
The curvature sensitive localization of proteins on membranes is vital for many cell biological p... more The curvature sensitive localization of proteins on membranes is vital for many cell biological processes. Coarse-grained models are routinely employed to study the curvature sensing phenomena and membrane morphology at the length scale of few micrometers. Two prevalent phenomenological models exist for modeling experimental observations of curvature sensing, (1) the spontaneous curvature model and (2) the curvature mismatch model, which differ in their treatment of the change in elastic energy due to the binding of proteins on the membrane. In this work, the prediction of sensing and generation behaviour, by these two models, are investigated using analytical calculations as well as Dynamic Triangulation Monte Carlo simulations of quasi-spherical vesicles. While the spontaneous curvature model yields a monotonically decreasing sensing curve as a function of vesicle radius, the curvature mismatch model results in a non-monotonic sensing curve. We highlight the main differences in the interpretation of the protein-related parameters in the two models. We further propose that the spontaneous curvature model is appropriate for modeling peripheral proteins employing the hydrophobic insertion mechanism, with minimal modification of membrane rigidity, while the curvature mismatch model is appropriate for modeling curvature generation using scaffolding mechanism where there is significant stiffening of the membrane due to protein binding.
Membrane curvature of a biological cell is actively involved in various fundamental cell biologic... more Membrane curvature of a biological cell is actively involved in various fundamental cell biological functions. It has been discovered that membrane curvature and binding of peripheral membrane proteins follow a symbiotic relationship. The exact mechanism behind this interplay of protein binding and membrane curvature has not yet been properly understood. To elucidate the mechanism, we study curvature sorting of proteins in a model system of a tether pulled from a Giant Unilamellar Vesicle (GUV) using mechanical-thermodynamic models. The concentration of proteins bound to membrane changes significantly due to curvature. This has also been observed in experiments by other researchers. We also find that there is a phase transition based on protein concentration and we discuss coexistence of phases and stability of solutions. Furthermore, when sorting is favorable, the increase in protein concentration stabilizes the tether in the sense that less pulling force is required to maintain the tether. A similar mechanism may be in place, when motor proteins pull tethers from donor membranes.
We study steady, fully developed, axisymmetric flows of soft, inelastic grains within a vertical ... more We study steady, fully developed, axisymmetric flows of soft, inelastic grains within a vertical circular pipe under the influence of gravity. We use extended kinetic theory to describe the collisional flow and include a region above the critical solid volume fraction near the center line that is the analog of an erodible bed. We calculate the profiles of velocity, shear stress, granular temperature, and particle concentration across the pipe for a variety of volume flow rates and pipe radii. We compare these with those measured in discrete element simulations by Barker et al. [J. Fluid Mech. 930, A21 (2022)] and see good agreement.
HAL (Le Centre pour la Communication Scientifique Directe), Nov 22, 2022
Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions rang... more Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions ranging from exocytosis to cell proliferation at different time scales. In the vasculature, a constant adenosine triphosphate (ATP) concentration is maintained because of ATP released by red blood cells (RBCs). These ATP molecules continuously react with purinergic receptors on the surface of endothelial cells (ECs). Consequently, a cascade of chemical reactions are triggered that result in a transient cytoplasmic calcium (Ca 2+), followed by return to its basal concentration. The mathematical models proposed in literature are able to reproduce the transient peak. However, the trailing concentration is always higher than the basal cytoplasmic Ca 2+ concentrations, and the Ca 2+ concentration in endoplasmic reticulum (ER) remains lower than its initial concentration. This means that the intracellular homeostasis is not recovered. We propose, herein, a minimal model of calcium kinetics. We find that the desensitization of EC surface receptors due to phosphorylation and recycling plays a vital role in maintaining calcium homeostasis in the presence of a constant stimulus (ATP). The model is able to capture several experimental observations such as refilling of Ca 2+ in the ER, variation of cytoplasmic Ca 2+ transient peak in ECs, the resting cytoplasmic Ca 2+ concentration, the effect of removing ATP from the plasma on Ca 2+ homeostasis, and the saturation of cytoplasmic Ca 2+ transient peak with increase in ATP concentration. Direct confrontation with several experimental results is conducted.This work paves the way to systematic studies for coupling between blood flow and chemical signaling, and should contribute to a better understanding of the relation between (patho)physiological conditions and Ca 2+ kinetics.
Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions rang... more Calcium is a ubiquitous molecule and second messenger that regulates many cellular functions ranging from exocytosis to cell proliferation at different time scales. In the vasculature, a constant adenosine triphosphate (ATP) concentration is maintained because of ATP released by red blood cells (RBCs). These ATP molecules continuously react with purinergic receptors on the surface of endothelial cells (ECs). Consequently, a cascade of chemical reactions are triggered that result in a transient cytoplasmic calcium (Ca 2+), followed by return to its basal concentration. The mathematical models proposed in literature are able to reproduce the transient peak. However, the trailing concentration is always higher than the basal cytoplasmic Ca 2+ concentrations, and the Ca 2+ concentration in endoplasmic reticulum (ER) remains lower than its initial concentration. This means that the intracellular homeostasis is not recovered. We propose, herein, a minimal model of calcium kinetics. We find that the desensitization of EC surface receptors due to phosphorylation and recycling plays a vital role in maintaining calcium homeostasis in the presence of a constant stimulus (ATP). The model is able to capture several experimental observations such as refilling of Ca 2+ in the ER, variation of cytoplasmic Ca 2+ transient peak in ECs, the resting cytoplasmic Ca 2+ concentration, the effect of removing ATP from the plasma on Ca 2+ homeostasis, and the saturation of cytoplasmic Ca 2+ transient peak with increase in ATP concentration. Direct confrontation with several experimental results is conducted.This work paves the way to systematic studies for coupling between blood flow and chemical signaling, and should contribute to a better understanding of the relation between (patho)physiological conditions and Ca 2+ kinetics.
Theoretical modeling of curvature induced sorting of cell-membrane proteins including soft intera... more Theoretical modeling of curvature induced sorting of cell-membrane proteins including soft interaction potentials, shape anisotropy, and curvature anisotropy.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2021
BACKGROUND Membrane-bound intracellular organelles have characteristic shapes attributed to diffe... more BACKGROUND Membrane-bound intracellular organelles have characteristic shapes attributed to different local membrane curvatures, and these attributes are conserved across species. Over the past decade, it has been confirmed that specific proteins control the large curvatures of the membrane, whereas many others due to their specific structural features can sense the curvatures and bind to the specific geometrical cues. Elucidating the interplay between sensing and induction is indispensable to understand the mechanisms behind various biological processes such as vesicular trafficking and budding. SCOPE OF REVIEW We provide an overview of major classes of membrane proteins and the mechanisms of curvature sensing and induction. We then discuss the importance of membrane elastic characteristics to induce the membrane shapes similar to intracellular organelles. Finally, we survey recently available assays developed for studying the curvature sensing and induction by many proteins. MAJOR CONCLUSIONS Recent theoretical/computational modeling along with experimental studies have uncovered fascinating connections between lipid membrane and protein interactions. However, the phenomena of protein localization and synchronization to generate spatiotemporal dynamics in membrane morphology are yet to be fully understood. GENERAL SIGNIFICANCE The understanding of protein-membrane interactions is essential to shed light on various biological processes. This further enables the technological applications of many natural proteins/peptides in therapeutic treatments. The studies of membrane dynamic shapes help to understand the fundamental functions of membranes, while the medicinal roles of various macromolecules (such as proteins, peptides, etc.) are being increasingly investigated.
The curvature sensitive localization of proteins on membranes is vital for many cell biological p... more The curvature sensitive localization of proteins on membranes is vital for many cell biological processes. Coarse-grained models are routinely employed to study the curvature sensing phenomena and membrane morphology at the length scale of few micrometers. Two prevalent phenomenological models exist for modeling experimental observations of curvature sensing, (1) the spontaneous curvature model and (2) the curvature mismatch model, which differ in their treatment of the change in elastic energy due to the binding of proteins on the membrane. In this work, the prediction of sensing and generation behaviour, by these two models, are investigated using analytical calculations as well as Dynamic Triangulation Monte Carlo simulations of quasi-spherical vesicles. While the spontaneous curvature model yields a monotonically decreasing sensing curve as a function of vesicle radius, the curvature mismatch model results in a non-monotonic sensing curve. We highlight the main differences in the interpretation of the protein-related parameters in the two models. We further propose that the spontaneous curvature model is appropriate for modeling peripheral proteins employing the hydrophobic insertion mechanism, with minimal modification of membrane rigidity, while the curvature mismatch model is appropriate for modeling curvature generation using scaffolding mechanism where there is significant stiffening of the membrane due to protein binding.
Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition ... more Grand canonical Monte Carlo simulations of the curvature sensing-curvature generation transition in vesicles.
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Papers by Sovan Das