scholarly journals Molecular Basis of the Activation and Dissociation of Dimeric PYL2 Receptor in Abscisic Acid Signaling

2019 ◽  
Author(s):  
Chuankai Zhao ◽  
Diwakar Shukla
Keyword(s):  
Free Energy ◽  
Abscisic Acid ◽  
Critical Role ◽  
Water Molecules ◽  
Plant Responses ◽  
Free Energy Barrier ◽  
Conformational Plasticity ◽  
Dynamics Simulations ◽  
Key Aspects ◽  
Aba Receptors

Phytohormone abscisic acid (ABA) is essential for plant responses to biotic and abiotic stresses. Dimeric receptors are a class of ABA receptors that are important for various ABA responses. While extensive experimental and computational studies have investigated these receptors, it remains not fully understood how ABA leads to their activation and dissociation for interaction with downstream phosphatase. It also remains unknown how networks of water molecules present in the binding site affect ABA perception despite its critical role in protein-ligand binding. Here, we study the activation and the homodimeric association processes of PYL2 receptor as well as its heterodimeric association with the phosphatase HAB1 using molecular dynamics simulations. Free energy landscapes from ~223 μs simulations show that dimerization substantially constrains PYL2 conformational plasticity and stabilizes inactive state, resulting in lower ABA affinity. Using hydration site analysis to characterize receptor solvation thermodynamics, we show that the displacement and reorganization of water molecules upon ABA binding contribute to binding affinity via gain of entropy and enthalpy, respectively. The penalty for expelling water molecules into the bulk causes the free energy barrier to binding (~4-5 kcal/mol). Finally, we establish the thermodynamic model for competitive binding between homodimeric PYL2 association and heterodimeric PYL2-HAB1 association in the absence and presence of ABA. Our results suggest that the binding of ABA destabilizes PYL2 complex and further stabilizes PYL2-HAB1 association, thereby promoting PYL2 dissociation. Overall, this study explains several key aspects on activation of dimeric ABA receptors, which provide new avenues for selective regulation of these receptors.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Thermodynamically reversible paths of the first fusion intermediate reveal an important role for membrane anchors of fusion proteins

2019 ◽  
Vol 116 (7) ◽  
pp. 2571-2576 ◽  
Author(s):  
Yuliya G. Smirnova ◽  
Herre Jelger Risselada ◽  
Marcus Müller
Keyword(s):  
Free Energy ◽  
Fusion Proteins ◽  
Biological Membrane ◽  
Fusion Reaction ◽  
Molecular Shape ◽  
Minimum Free Energy ◽  
Spontaneous Curvature ◽  
Free Energy Barrier ◽  
Lipid Species ◽  
Dynamics Simulations

Biological membrane fusion proceeds via an essential topological transition of the two membranes involved. Known players such as certain lipid species and fusion proteins are generally believed to alter the free energy and thus the rate of the fusion reaction. Quantifying these effects by theory poses a major challenge since the essential reaction intermediates are collective, diffusive and of a molecular length scale. We conducted molecular dynamics simulations in conjunction with a state-of-the-art string method to resolve the minimum free-energy path of the first fusion intermediate state, the so-called stalk. We demonstrate that the isolated transmembrane domains (TMDs) of fusion proteins such as SNARE molecules drastically lower the free energy of both the stalk barrier and metastable stalk, which is not trivially explained by molecular shape arguments. We relate this effect to the local thinning of the membrane (negative hydrophobic mismatch) imposed by the TMDs which favors the nearby presence of the highly bent stalk structure or prestalk dimple. The distance between the membranes is the most crucial determinant of the free energy of the stalk, whereas the free-energy barrier changes only slightly. Surprisingly, fusion enhancing lipids, i.e., lipids with a negative spontaneous curvature, such as PE lipids have little effect on the free energy of the stalk barrier, likely because of its single molecular nature. In contrast, the lipid shape plays a crucial role in overcoming the hydration repulsion between two membranes and thus rather lowers the total work required to form a stalk.

scholarly journals Dynamic Properties of Water Confined in Graphene-Based Membrane: A Classical Molecular Dynamics Simulation Study

Membranes ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 165 ◽  
Author(s):  
One-Sun Lee
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Graphene Sheets ◽  
Water Molecules ◽  
Energy Profile ◽  
Confined Water ◽  
Graphene Surface ◽  
Dynamics Simulations ◽  
Density Of Water

We performed molecular dynamics simulations of water molecules inside a hydrophobic membrane composed of stacked graphene sheets. By decreasing the density of water molecules inside the membrane, we observed that water molecules form a droplet through a hydrogen bond with each other in the hydrophobic environment that stacked graphene sheets create. We found that the water droplet translates as a whole body rather than a dissipate. The translational diffusion coefficient along the graphene surface increases as the number of water molecules in the droplet decreases, because the bigger water droplet has a stronger van der Waals interaction with the graphene surface that hampers the translational motion. We also observed a longer hydrogen bond lifetime as the density of water decreased, because the hydrophobic environment limits the libration motion of the water molecules. We also calculated the reorientational correlation time of the water molecules, and we found that the rotational motion of confined water inside the membrane is anisotropic and the reorientational correlation time of confined water is slower than that of bulk water. In addition, we employed steered molecular dynamics simulations for guiding the target molecule, and measured the free energy profile of water and ion penetration through the interstice between graphene sheets. The free energy profile of penetration revealed that the optimum interlayer distance for desalination is ~10 Å, where the minimum distance for water penetration is 7 Å. With a 7 Å interlayer distance between the graphene sheets, water molecules are stabilized inside the interlayer space because of the van der Waals interaction with the graphene sheets where sodium and chloride ions suffer from a 3–8 kcal/mol energy barrier for penetration. We believe that our simulation results would be a significant contribution for designing a new graphene-based membrane for desalination.

scholarly journals Competitive dewetting underlies site-specific binding of general anesthetics to GABA(A) receptors

2019 ◽  
Author(s):  
Sruthi Murlidaran ◽  
Jérôme Hénin ◽  
Grace Brannigan
Keyword(s):  
Free Energy ◽  
Binding Sites ◽  
Critical Role ◽  
Free Energy Calculations ◽  
Water Molecules ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Water Displacement ◽  
Gaba A ◽  
Acyl Chains

AbstractGABA(A) receptors are pentameric ligand-gated ion channels playing a critical role in the modulation of neuronal excitability. These inhibitory receptors, gated by γ-aminobutyric acid (GABA), can be potentiated and even directly activated by intravenous and inhalational anesthetics. Intersubunit cavities in the transmembrane domain have been consistently identified as putative binding sites by numerous experiment and simulation results. Synaptic GABA(A) receptors are predominantly found in a 2α:2β:1γ stoichiometry, with four unique inter-subunit interfaces. Experimental and computational results have suggested a perplexing specificity, given that cavity-lining residues are highly conserved, and the functional effects of general anesthetics are only weakly sensitive to most mutations of cavity residues. Here we use Molecular Dynamics simulations and thermodynamically rigorous alchemical free energy perturbation (AFEP) techniques to calculate affinities of the intravenous anesthetic propofol and the inhaled anesthetic sevoflurane to all intersubunit sites in a heteromeric GABA(A) receptor. We find that the best predictor of general anesthetic affinity for the intersubunit cavity sites is water displacement: combinations of anesthetic and binding site that displace more water molecules have higher affinities than those that displace fewer. The amount of water displacement is, in turn, a function of size of the general anesthetic, successful competition of the general anesthetic with water for the few hydrogen bonding partners in the site, and inaccessibility of the site to lipid acyl chains. The latter explains the surprisingly low affinity of GAs for the γ − α intersubunit site, which is missing a bulky methionine residue at the cavity entrance and can be occupied by acyl chains in the unbound state. Simulations also identify sevoflurane binding sites in the β subunit centers and in the pore, but predict that these are lower affinity than the intersubunit sites.SignificanceAfter over a century of research, it is established that general anesthetics interact directly with hydrophobic cavities in proteins. We still do not know why not all small hydrophobic molecules can act as general anesthetics, or why not all hydrophobic cavities bind these molecules. General anesthetics can even select among homologous sites on one critical target, the GABA(A) heteropentamer, although the origins of selectivity are unknown. Here we used rigorous free energy calculations to find that binding affinity correlates with the number of released water molecules, which in turn depends upon the lipid content of the cavity without bound anesthetic. Results suggest a mechanism that reconciles lipid-centered and protein-centered theories, and which can directly inform design of new anesthetics.

scholarly journals Intriguing Role of Water in Plant Hormone Perception

2021 ◽  
Author(s):  
Chuankai Zhao ◽  
Diego Eduardo Kleiman ◽  
Diwakar Shukla
Keyword(s):  
Free Energy ◽  
Plant Growth ◽  
Binding Site ◽  
Plant Hormones ◽  
Plant Hormone ◽  
Water Molecules ◽  
Water Displacement ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncov- ers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals The histone H3 N-terminal tail: a computational analysis of the free energy landscape and kinetics

2015 ◽  
Vol 17 (20) ◽  
pp. 13689-13698 ◽  
Author(s):  
Yuqing Zheng ◽  
Qiang Cui
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Critical Role ◽  
Histone H3 ◽  
Free Energy Landscape ◽  
Chromatin Dynamics ◽  
Markov State Models ◽  
State Models ◽  
Dynamics Simulations ◽  
Kinetics Of

Extensive molecular dynamics simulations and Markov State models are used to characterize the free energy landscape and kinetics of the histone H3 N-terminal tail, which plays a critical role in regulating chromatin dynamics and gene activity.

scholarly journals Effects of lipid composition on membrane distribution and permeability of natural quinones

2019 ◽  
Author(s):  
Murilo Hoias Teixeira ◽  
Guilherme Menegon Arantes
Keyword(s):  
Free Energy ◽  
Lipid Composition ◽  
Proton Translocation ◽  
Acyl Chain ◽  
Free Energy Calculations ◽  
Free Energy Barrier ◽  
Water Penetration ◽  
Amphiphilic Molecules ◽  
Dynamics Simulations

ABSTRACTNatural quinones are amphiphilic molecules that function as mobile charge carriers in biological energy transduction. Their distribution and permeation across membranes are important for binding to enzymatic complexes and for proton translocation. Here, we employ molecular dynamics simulations and free energy calculations with a carefully calibrated classical force-field to probe quinone distribution and permeation in a multicomponent bilayer trying to mimic the composition of membranes involved in bioenergetic processes. Ubiquinone, ubiquinol, plastoquinone and menaquinone molecules with short and long isoprenoid tails are simulated. We find that water penetration increases considerably in the less ordered and porous bilayer formed by di-linoleoyl (18:2) phospholipids, resulting in a lower free energy barrier for quinone permeation and faster transversal diffusion. In equilibrium, quinone and quinol heads localize preferentially near lipid glycerol groups, but do not perform specific contacts with lipid polar heads. Quinone distribution is not altered significantly by the quinone head, tail and lipid composition in comparison to a single-component bilayer. This study highlights the role of acyl chain unsaturation for molecular permeation and transversal diffusion across biological membranes.

scholarly journals Molecular Dynamics Simulations of the “Breathing” Phase Transformation of MOF Nanocrystallites

2019 ◽  
Author(s):  
Julian Keupp ◽  
Rochus Schmid
Keyword(s):  
Free Energy ◽  
Phase Transformation ◽  
Surface Effect ◽  
Umbrella Sampling ◽  
Distance Restraint ◽  
Free Energy Barrier ◽  
The One ◽  
Dynamics Simulations ◽  
The Impact ◽  
Closed Pore

One of the intriguing features of certain metal-organic frameworks (MOFs) is the large volume change upon external stimuli like pressure or guest molecule adsorption, referred to as “breathing”. This displacive phase transformation from an open to a closed pore has been investigated intensively by theoretical simulations within periodic boundary conditions (PBC). However, the actual free energy barriers for the transformation under real conditions and the impact of surface effects on it can only be studied beyond PBC for nanocrystallites. In this work, we used the first-principles parameterized forcefield MOF-FF to investigate the thermal- and pressure induced transformations for nanocrystallites of the pillared-layer DMOF-1 (Zn<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(bdc)<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(dabco); bdc: 1,4-benzenedicarboxylate; dabco: 1,4-diazabicyclo[2.2.2]octane) as a model system. By heating of prepared closed pore nanocrystallites of different size, a spontaneous opening is observed within a few tenth of picoseconds with an interface between the closed and open pore phase moving with a velocity of several 100 m/s<math><mrow><mrow><mi></mi> </mrow><mrow><mi></mi> </mrow> </mrow></math> through the system. The critical nucleation temperature for the opening transition raises with size. On the other hand, by forcing the closing transition with a distance restraint between paddle-wheel units placed on opposite edges of the crystallite, the free energy barrier can be determined by umbrella sampling. As expected, this barrier is substantially lower than the one determined for a concerted process under PBC. Interestingly, the barrier reduces with the size of the crystallite, indicating a hindering surface effect. The results demonstrate the need consider domain boundaries and surfaces, for example by simulations that go beyond PBC and to large system sizes in order to properly predict and describe first order phase transitions in MOFs.<div> </div>

scholarly journals Molecular Dynamics Simulations of the “Breathing” Phase Transformation of MOF Nanocrystallites

2019 ◽  
Author(s):  
Julian Keupp ◽  
Rochus Schmid
Keyword(s):  
Free Energy ◽  
Phase Transformation ◽  
Surface Effect ◽  
Umbrella Sampling ◽  
Distance Restraint ◽  
Free Energy Barrier ◽  
The One ◽  
Dynamics Simulations ◽  
The Impact ◽  
Closed Pore

One of the intriguing features of certain metal-organic frameworks (MOFs) is the large volume change upon external stimuli like pressure or guest molecule adsorption, referred to as “breathing”. This displacive phase transformation from an open to a closed pore has been investigated intensively by theoretical simulations within periodic boundary conditions (PBC). However, the actual free energy barriers for the transformation under real conditions and the impact of surface effects on it can only be studied beyond PBC for nanocrystallites. In this work, we used the first-principles parameterized forcefield MOF-FF to investigate the thermal- and pressure induced transformations for nanocrystallites of the pillared-layer DMOF-1 (Zn<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(bdc)<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(dabco); bdc: 1,4-benzenedicarboxylate; dabco: 1,4-diazabicyclo[2.2.2]octane) as a model system. By heating of prepared closed pore nanocrystallites of different size, a spontaneous opening is observed within a few tenth of picoseconds with an interface between the closed and open pore phase moving with a velocity of several 100 m/s<math><mrow><mrow><mi></mi> </mrow><mrow><mi></mi> </mrow> </mrow></math> through the system. The critical nucleation temperature for the opening transition raises with size. On the other hand, by forcing the closing transition with a distance restraint between paddle-wheel units placed on opposite edges of the crystallite, the free energy barrier can be determined by umbrella sampling. As expected, this barrier is substantially lower than the one determined for a concerted process under PBC. Interestingly, the barrier reduces with the size of the crystallite, indicating a hindering surface effect. The results demonstrate the need consider domain boundaries and surfaces, for example by simulations that go beyond PBC and to large system sizes in order to properly predict and describe first order phase transitions in MOFs.<div> </div>

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