The 'allosteron' model for entropic allostery of self-assembly.
Ontology highlight
ABSTRACT:
SUBMITTER: McLeish T
PROVIDER: S-EPMC5941180 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
Publications
The 'allosteron' model for entropic allostery of self-assembly.
McLeish Tom T Schaefer C C von der Heydt A C AC
Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20180601 1749
Using the simple 'allosteron' model, we show that it is possible, in principle, to elicit pathways by which fluctuation allostery affects self-assembly of protein complexes. We treat the cases of (i) protein fibrils and nucleation, (ii) <i>n</i>-mer protein complexes, and (iii) weakly attractive allosteric interactions in protein-like soft nanoscale objects that can be tuned to define exclusive self-associating families.This article is part of a discussion meeting issue 'Allostery and molecular ...[more]
Similar Datasets
Project description:Molecular self-assembly refers to the spontaneous assembly of molecules into larger structures. In order to exploit molecular self-assembly for the bottom-up synthesis of nanomaterials, the effects of chemical control (strength of the directionality in the intermolecular interaction) and entropic control (temperature) on the self-assembly process should be clarified. Here we present a theoretical methodology that unambiguously distinguishes the effects of chemical and entropic control on the self-assembly of molecules adsorbed to metal surfaces. While chemical control simply increases the formation probability of ordered structures, entropic control induces a variety of effects. These effects range from fine structure modulation of ordered structures, through to degrading large, amorphous structures into short, chain-shaped structures. Counterintuitively, the latter effect shows that entropic control can improve molecular ordering. By identifying appropriate levels of chemical and entropic control, our methodology can, therefore, identify strategies for optimizing the yield of desired nanostructures from the molecular self-assembly process.
| S-EPMC5316874 | biostudies-literature
Project description:Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier's principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.
| S-EPMC4846164 | biostudies-literature
Project description:Assembly of virus capsids and surface proteins must be regulated to ensure that the resulting complex is an infectious virion. In this review, we examine assembly of virus capsids, focusing on hepatitis B virus and bacteriophage MS2, and formation of glycoproteins in the alphaviruses. These systems are structurally and biochemically well-characterized and are simplest-case paradigms of self-assembly. Published data suggest that capsid and glycoprotein assembly is subject to allosteric regulation, that is regulation at the level of conformational change. The hypothesis that allostery is a common theme in viruses suggests that deregulation of capsid and glycoprotein assembly by small molecule effectors will be an attractive antiviral strategy, as has been demonstrated with hepatitis B virus.
| S-EPMC3026312 | biostudies-literature
Project description:Spleen tyrosine kinase (Syk) is an essential player in immune signaling through its ability to couple multiple classes of membrane immunoreceptors to intracellular signaling pathways. Ligand binding leads to the recruitment of Syk to a phosphorylated cytoplasmic region of the receptors called ITAM. Syk binds to ITAM with high-affinity (nanomolar Kd ) via its tandem pair of SH2 domains. The affinity between Syk and ITAM is allosterically regulated by phosphorylation at Y130 in a linker connecting the tandem SH2 domains; when Y130 is phosphorylated, the binding affinity decreases (micromolar Kd ). Previous equilibrium binding studies attribute the increase in the binding free energy to an intra-molecular binding (isomerization) step of the tandem SH2 and ITAM, but a physical basis for the increased free energy is unknown. Here, we provide evidence that Y130 phosphorylation imposes an entropy penalty to isomerization, but surprisingly, has negligible effect on the SH2 binding interactions with ITAM and thus on the binding enthalpy. An analysis of NMR chemical shift differences characterized conformational effects of ITAM binding, and binding thermodynamics were measured from isothermal titration calorimetry. Together the data support a previously unknown mechanism for the basis of regulating protein-protein interactions through protein phosphorylation. The decreased affinity for Syk association with immune receptor ITAMs by Y130 phosphorylation is an allosteric mechanism driven by an increased entropy penalty, likely contributed by conformational disorder in the SH2-SH2 inter-domain structure, while SH2-ITAM binding contacts are not affected, and binding enthalpy is unchanged.
| S-EPMC6225982 | biostudies-literature
Project description:Here, we report an engineering approach toward multicomponent self-assembly processes by developing a methodology to circumvent spurious, metastable assemblies. The formation of metastable aggregates often hampers self-assembly of molecular building blocks into the desired nanostructures. Strategies are explored to master the pathway complexity and avoid off-pathway aggregates by optimizing the rate of assembly along the correct pathway. We study as a model system the coassembly of two monomers, the R- and S-chiral enantiomers of a ?-conjugated oligo(p-phenylene vinylene) derivative. Coassembly kinetics are analyzed by developing a kinetic model, which reveals the initial assembly of metastable structures buffering free monomers and thereby slows the formation of thermodynamically stable assemblies. These metastable assemblies exert greater influence on the thermodynamically favored self-assembly pathway if the ratio between both monomers approaches 1:1, in agreement with experimental results. Moreover, competition by metastable assemblies is highly temperature dependent and hampers the assembly of equilibrium nanostructures most effectively at intermediate temperatures. We demonstrate that the rate of the assembly process may be optimized by tuning the cooling rate. Finally, it is shown by simulation that increasing the driving force for assembly stepwise by changing the solvent composition may circumvent metastable pathways and thereby force the assembly process directly into the correct pathway.
| S-EPMC3808594 | biostudies-literature
Project description:RING domains act in a variety of essential cellular processes but have no general function ascribed to them. Here, we observe that purified arenaviral protein Z, constituted almost entirely by its RING domain, self-assembles in vitro into spherical structures that resemble functional bodies formed by Z in infected cells. By using a variety of biophysical methods we provide a thermodynamic and kinetic framework for the RING-dependent self-assembly of Z. Assembly appears coupled to substantial conformational reorganization and changes in zinc coordination of site II of the RING. Thus, the rate-limiting nature of conformational reorganization observed in the folding of monomeric proteins can also apply to the assembly of macromolecular scaffolds. These studies describe a unique mechanism of nonfibrillar homogeneous self-assembly and suggest a general function of RINGs in the formation of macromolecular scaffolds that are positioned to integrate biochemical processes in cells.
| S-EPMC117363 | biostudies-literature
Project description:We consider self-assembly of proteins into a virus capsid by the methods of molecular dynamics. The capsid corresponds either to SPMV or CCMV and is studied with and without the RNA molecule inside. The proteins are flexible and described by the structure-based coarse-grained model augmented by electrostatic interactions. Previous studies of the capsid self-assembly involved solid objects of a supramolecular scale, e.g. corresponding to capsomeres, with engineered couplings and stochastic movements. In our approach, a single capsid is dissociated by an application of a high temperature for a variable period and then the system is cooled down to allow for self-assembly. The restoration of the capsid proceeds to various extent, depending on the nature of the dissociated state, but is rarely complete because some proteins depart too far unless the process takes place in a confined space.
| S-EPMC7104874 | biostudies-literature
Project description:The bottom-up synthesis of artificial, life-like systems promises to enable the study of emergent properties distinctive to life. Here, we report protocell systems generated from phase-separated building blocks. Vesicle protocells self-reproduce through a phase-transfer mechanism, catalysing their own formation. Dissipative self-assembly by the protocells is achieved when a hydrolysis step to destroy the surfactant is introduced. Competition between micelle and vesicle based replicators for a common feedstock shows that environmental conditions can control what species predominates: under basic conditions vesicles predominate, but in a neutral medium micelles are selected for via a mechanism which inhibits vesicle formation. Finally, the protocells enable orthogonal reactivity by catalysing in situ formation of an amphiphilic organocatalyst, which after incorporation into the vesicle bilayer enantioselectively forms a secondary product.
| S-EPMC8162124 | biostudies-literature
Project description:The properties of biological networks, such as those found in the ocular lens capsule, are difficult to study without simplified models. Model polymers are developed, inspired by "worm-like" curve models, that are shown to spontaneously self assemble to form networks similar to those observed experimentally in biological systems. These highly simplified coarse-grained models allow the self assembly process to be studied on near-realistic time-scales. Metrics are developed (using a polygon-based framework) which are useful for describing simulated networks and can also be applied to images of real networks. These metrics are used to show the range of control that the computational polymer model has over the networks, including the polygon structure and short range order. The structure of the simulated networks are compared to previous simulation work and microscope images of real networks. The network structure is shown to be a function of the interaction strengths, cooling rates and external pressure. In addition, "pre-tangled" network structures are introduced and shown to significantly influence the subsequent network structure. The network structures obtained fit into a region of the network landscape effectively inaccessible to random (entropically-driven) networks but which are occupied by experimentally-derived configurations.
| S-EPMC7918283 | biostudies-literature
Project description:SNARE proteins are the core of the cell's fusion machinery and mediate virtually all known intracellular membrane fusion reactions on which exocytosis and trafficking depend. Fusion is catalyzed when vesicle-associated v-SNAREs form trans-SNARE complexes ("SNAREpins") with target membrane-associated t-SNAREs, a zippering-like process releasing ∼65 kT per SNAREpin. Fusion requires several SNAREpins, but how they cooperate is unknown and reports of the number required vary widely. To capture the collective behavior on the long timescales of fusion, we developed a highly coarse-grained model that retains key biophysical SNARE properties such as the zippering energy landscape and the surface charge distribution. In simulations the ∼65-kT zippering energy was almost entirely dissipated, with fully assembled SNARE motifs but uncomplexed linker domains. The SNAREpins self-organized into a circular cluster at the fusion site, driven by entropic forces that originate in steric-electrostatic interactions among SNAREpins and membranes. Cooperative entropic forces expanded the cluster and pulled the membranes together at the center point with high force. We find that there is no critical number of SNAREs required for fusion, but instead the fusion rate increases rapidly with the number of SNAREpins due to increasing entropic forces. We hypothesize that this principle finds physiological use to boost fusion rates to meet the demanding timescales of neurotransmission, exploiting the large number of v-SNAREs available in synaptic vesicles. Once in an unfettered cluster, we estimate ≥15 SNAREpins are required for fusion within the ∼1-ms timescale of neurotransmitter release.
| S-EPMC5448213 | biostudies-literature