An allosteric mechanism inferred from molecular dynamics simulations on phospholamban pentamer in lipid membranes.
Ontology highlight
ABSTRACT:
SUBMITTER: Lian P
PROVIDER: S-EPMC3078132 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
An allosteric mechanism inferred from molecular dynamics simulations on phospholamban pentamer in lipid membranes.
Lian Peng P Wei Dong-Qing DQ Wang Jing-Fang JF Chou Kuo-Chen KC
PloS one 20110415 4
Phospholamban functions as a regulator of Ca(2+) concentration of cardiac muscle cells by triggering the bioactivity of sarcoplasmic reticulum Ca(2+)-ATPase. In order to understand its dynamic mechanism in the environment of bilayer surroundings, we performed long time-scale molecular dynamic simulations based on the high-resolution NMR structure of phospholamban pentamer. It was observed from the molecular dynamics trajectory analyses that the conformational transitions between the "bellflower" ...[more]
Similar Datasets
Project description:A 52-residue membrane protein, phospholamban (PLN) is an inhibitor of an adenosine-5'-triphosphate-driven calcium pump, the Ca2+-ATPase. Although the inhibition of Ca2+-ATPase involves PLN monomers, in a lipid bilayer membrane, PLN monomers form stable pentamers of unknown biological function. The recent NMR structure of a PLN pentamer depicts cytoplasmic helices extending normal to the bilayer in what is known as the bellflower conformation. The structure shows transmembrane helices forming a hydrophobic pore 4 A in diameter, which is reminiscent of earlier reports of possible ion conductance through PLN pentamers. However, recent FRET measurements suggested an alternative structure for the PLN pentamer, known as the pinwheel model, which features a narrower transmembrane pore and cytoplasmic helices that lie against the bilayer. Here, we report on structural dynamics and conductance properties of the PLN pentamers from all-atom (AA) and coarse-grained (CG) molecular dynamics simulations. Our AA simulations of the bellflower model demonstrate that in a lipid bilayer membrane or a detergent micelle, the cytoplasmic helices undergo large structural fluctuations, whereas the transmembrane pore shrinks and becomes asymmetric. Similar asymmetry of the transmembrane region was observed in the AA simulations of the pinwheel model; the cytoplasmic helices remained in contact with the bilayer. Using the CG approach, structural dynamics of both models were investigated on a microsecond timescale. The cytoplasmic helices of the CG bellflower model were observed to fall against the bilayer, whereas in the CG pinwheel model the conformation of the cytoplasmic helices remained stable. Using steered molecular dynamics simulations, we investigated the feasibility of ion conductance through the pore of the bellflower model. The resulting approximate potentials of mean force indicate that the PLN pentamer is unlikely to function as an ion channel.
| S-EPMC2712031 | biostudies-literature
Project description:Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.
| S-EPMC3531320 | biostudies-literature
Project description:The recombinant HIV-1 Tat protein contains a small region corresponding to residues (47)YGRKKRRQRR(57)R, which is capable of translocating cargoes of different molecular sizes, such as proteins, DNA, RNA, or drugs, across the cell membrane in an apparently energy-independent manner. The pathway that these peptides follow for entry into the cell has been the subject of strong controversy for the last decade. This peptide is highly basic and hydrophilic. Therefore, a central question that any candidate mechanism has to answer is how this highly hydrophilic peptide is able to cross the hydrophobic barrier imposed by the cell membrane. We propose a mechanism for the spontaneous translocation of the Tat peptides across a lipid membrane. This mechanism involves strong interactions between the Tat peptides and the phosphate groups on both sides of the lipid bilayer, the insertion of charged side chains that nucleate the formation of a transient pore, followed by the translocation of the Tat peptides by diffusing on the pore surface. This mechanism explains how key ingredients, such as the cooperativity among the peptides, the large positive charge, and specifically the arginine amino acids, contribute to the uptake. The proposed mechanism also illustrates the importance of membrane fluctuations. Indeed, mechanisms that involve large fluctuations of the membrane structure, such as transient pores and the insertion of charged amino acid side chains, may be common and perhaps central to the functions of many membrane protein functions.
| S-EPMC2409222 | biostudies-literature
Project description:Contraction and relaxation of heart muscle cells is regulated by cycling of calcium between cytoplasm and sarcoplasmic reticulum. Human phospholamban (PLN), expressed in the sarcoplasmic reticulum membrane as a 30-kDa homopentamer, controls cellular calcium levels by a mechanism that depends on its phosphorylation. Since PLN was discovered approximately 30 years ago, extensive studies have aimed to explain how it influences calcium pumps and to determine whether it acts as an ion channel. We have determined by solution NMR methods the atomic resolution structure of an unphosphorylated PLN pentamer in dodecylphosphocholine micelles. The unusual bellflower-like assembly is held together by leucine/isoleucine zipper motifs along the membrane-spanning helices. The structure reveals a channel-forming architecture that could allow passage of small ions. The central pore gradually widens toward the cytoplasmic end as the transmembrane helices twist around each other and bend outward. The dynamic N-terminal amphipathic helices point away from the membrane, perhaps facilitating recognition and inhibition of the calcium pump.
| S-EPMC1182456 | biostudies-literature
Project description:It is still difficult to obtain a precise structural description of the transition between the deoxy T-state and oxy R-state conformations of human hemoglobin, despite a large number of experimental studies. We used molecular dynamics with the Path Exploration with Distance Constraints (PEDC) method to provide new insights into the allosteric mechanism at the atomic level, by simulating the T-to-R transition. The T-state molecule in the absence of ligands was seen to have a natural propensity for dimer rotation, which nevertheless would be hampered by steric hindrance in the "joint" region. The binding of a ligand to the alpha subunit would prevent such hindrance due to the coupling between this region and the alpha proximal histidine, and thus facilitate completion of the dimer rotation. Near the end of this quaternary transition, the "switch" region adopts the R conformation, resulting in a shift of the beta proximal histidine. This leads to a sliding of the beta-heme, the effect of which is to open the beta-heme's distal side, increasing the accessibility of the Fe atom and thereby the affinity of the protein. Our simulations are globally consistent with the Perutz strereochemical mechanism.
| S-EPMC1302112 | biostudies-other
Project description:The bacterial adhesin FimH consists of an allosterically regulated mannose-binding lectin domain and a covalently linked inhibitory pilin domain. Under normal conditions, the two domains are bound to each other, and FimH interacts weakly with mannose. However, under tensile force, the domains separate and the lectin domain undergoes conformational changes that strengthen its bond with mannose. Comparison of the crystallographic structures of the low and the high affinity state of the lectin domain reveals conformational changes mainly in the regulatory inter-domain region, the mannose binding site and a large ? sheet that connects the two distally located regions. Here, molecular dynamics simulations investigated how conformational changes are propagated within and between different regions of the lectin domain. It was found that the inter-domain region moves towards the high affinity conformation as it becomes more compact and buries exposed hydrophobic surface after separation of the pilin domain. The mannose binding site was more rigid in the high affinity state, which prevented water penetration into the pocket. The large central ? sheet demonstrated a soft spring-like twisting. Its twisting motion was moderately correlated to fluctuations in both the regulatory and the binding region, whereas a weak correlation was seen in a direct comparison of these two distal sites. The results suggest a so called "population shift" model whereby binding of the lectin domain to either the pilin domain or mannose locks the ? sheet in a rather twisted or flat conformation, stabilizing the low or the high affinity state, respectively. Proteins 2016; 84:990-1008. © 2016 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.
| S-EPMC5084802 | biostudies-literature
Project description:The sequence-dependent DNA deformability at the basepair step level was investigated using large-scale atomic resolution molecular dynamics simulation of two 18-bp DNA oligomers: d(GCCTATAAACGCCTATAA) and d(CTAGGTGGATGACTCATT). From an analysis of the structural fluctuations, the harmonic potential energy functions for all 10 unique steps with respect to the six step parameters have been evaluated. In the case of roll, three distinct groups of steps have been identified: the flexible pyrimidine-purine (YR) steps, intermediate purine-purine (RR), and stiff purine-pyrimidine (RY). The YR steps appear to be the most flexible in tilt and partially in twist. Increasing stiffness from YR through RR to RY was observed for rise, whereas shift and slide lack simple trends. A proposed measure of the relative importance of couplings identifies the slide-rise, twist-roll, and twist-slide couplings to play a major role. The force constants obtained are of similar magnitudes to those based on a crystallographic ensemble. However, the current data have a less complicated and less pronounced sequence dependence. A correlation analysis reveals concerted motions of neighboring steps and thus exposes limitations in the dinucleotide model. The comparison of DNA deformability from this and other studies with recent quantum-chemical stacking energy calculations suggests poor correlation between the stacking and flexibility.
| S-EPMC1303568 | biostudies-literature
Project description:The extent to which current force fields faithfully reproduce conformational properties of lipids in bilayer membranes, and whether these reflect the structural principles established for phospholipids in bilayer crystals, are central to biomembrane simulations. We determine the distribution of dihedral angles in palmitoyl-oleoyl phosphatidylcholine from molecular dynamics simulations of hydrated fluid bilayer membranes. We compare results from the widely used lipid force field of Berger et al. with those from the most recent C36 release of the CHARMM force field for lipids. Only the CHARMM force field produces the chain inequivalence with sn-1 as leading chain that is characteristic of glycerolipid packing in fluid bilayers. The exposure and high partial charge of the backbone carbonyls in Berger lipids leads to artifactual binding of Na+ ions reported in the literature. Both force fields predict coupled, near-symmetrical distributions of headgroup dihedral angles, which is compatible with models of interconverting mirror-image conformations used originally to interpret NMR order parameters. The Berger force field produces rotamer populations that correspond to the headgroup conformation found in a phosphatidylcholine lipid bilayer crystal, whereas CHARMM36 rotamer populations are closer to the more relaxed crystal conformations of phosphatidylethanolamine and glycerophosphocholine. CHARMM36 alone predicts the correct relative signs of the time-average headgroup order parameters, and reasonably reproduces the full range of NMR data from the phosphate diester to the choline methyls. There is strong motivation to seek further experimental criteria for verifying predicted conformational distributions in the choline headgroup, including the 31P chemical shift anisotropy and 14N and CD3 NMR quadrupole splittings.
| S-EPMC5937052 | biostudies-literature
Project description:Molecular dynamics (MD) simulations of membranes are often hindered by the slow lateral diffusion of lipids and the limited time scale of MD. In order to study the dynamics of mixing and characterize the lateral distribution of lipids in converged mixtures, we report microsecond-long all-atom MD simulations performed on the special-purpose machine Anton. Two types of mixed bilayers, POPE:POPG (3:1) and POPC:cholesterol (2:1), as well as a pure POPC bilayer, were each simulated for up to 2 μs. These simulations show that POPE:POPG and POPC:cholesterol are each fully miscible at the simulated conditions, with the final states of the mixed bilayers similar to a random mixture. By simulating three POPE:POPG bilayers at different NaCl concentrations (0, 0.15, and 1 M), we also examined the effect of salt concentration on lipid mixing. While an increase in NaCl concentration is shown to affect the area per lipid, tail order, and lipid lateral diffusion, the final states of mixing remain unaltered, which is explained by the largely uniform increase in Na(+) ions around POPE and POPG. Direct measurement of water permeation reveals that the POPE:POPG bilayer with 1 M NaCl has reduced water permeability compared with those at zero or low salt concentration. Our calculations provide a benchmark to estimate the convergence time scale of all-atom MD simulations of lipid mixing. Additionally, equilibrated structures of POPE:POPG and POPC:cholesterol, which are frequently used to mimic bacterial and mammalian membranes, respectively, can be used as starting points of simulations involving these membranes.
| S-EPMC4196744 | biostudies-literature
Project description:Aggregation of amyloid-[Formula: see text] (A?) peptides, cleaved from the amyloid precursor protein, is known as a precursor of the Alzheimer's disease (AD). It is also known that Alzheimer's disease is characterized by a substantial decrease of the amount of polyunsaturated lipids in the neuronal membranes of the frontal gray matter. To get insight into possible interconnection of these phenomena, we have carried out molecular dynamics simulations of two fragments of A[Formula: see text] peptide, A[Formula: see text][Formula: see text] and A[Formula: see text][Formula: see text], in four different lipid bilayers: two monocomponent ones (14:0-14:0 PC, 18:0-22:6 PC), and two bilayers containing mixtures of 18:0-18:0 PE, 22:6-22:6 PE, 16:0-16:0 PC and 18:1-18:1 PC lipids of composition mimicking neuronal membranes in a "healthy" and "AD" brain. The simulations showed that the presence of lipids with highly unsaturated 22:6cis fatty acids chains strongly affects the interaction of amyloid-[Formula: see text] peptides with lipid membranes. The polyunsaturated lipids cause stronger adsorption of A[Formula: see text]-peptides by the membrane and lead to weaker binding between peptides when the latter form aggregates. This difference in the behaviour observed in monocomponent bilayers is propagated in a similar fashion to the mixed membranes mimicking composition of neuronal membranes in "healthy" and "AD" brains, with "healthy" membrane having higher fraction of polyunsaturated lipids. Our simulations give strong indication that it can be physical-chemical background of the interconnection between amyloid fibrillization causing Alzheimer's disease, and content of polyunsaturated lipids in the neuronal membranes.
| S-EPMC6853862 | biostudies-literature