scholarly journals Translocation process of structured polypeptides across nanopores

2010 ◽  
Vol 24 (3-4) ◽  
pp. 421-426 ◽  
Author(s):  
Fabio Cecconi ◽  
Umberto Marini Bettolo Marconi ◽  
Angelo Vulpiani
Keyword(s):  
Statistical Physics ◽  
Coarse Grained ◽  
Free Energy Barrier ◽  
Transport Dynamics ◽  
Alpha Hemolysin ◽  
Translocation Mechanism ◽  
Smoluchowski Equations ◽  
Pulling Force ◽  
Molecular Manipulation ◽  
Polypeptide Chains

The progress of molecular manipulation technology has made it possible to conduct controlled experiments on translocation of polynucleotide and polypeptide chains across alpha-Hemolysin channels and solid-state nanopores. To study the translocation process we combined Molecular Dynamics at coarse-grained level and appropriate drift-diffusion Smoluchowski equations as an integrated statistical physics approach. In particular, we performed simulations of the passage across a cylindrical nanopore of Ubiquitin described by a coarse-grained native-centric model to investigate the influence of protein structural properties on translocation mechanism. The kinetic characterization of the process is achieved by studying the statistics of blockage times, the mobility and translocation probability as a function of the pulling forceFacting in the pore. We find that the transport dynamics displays a thresholdFcdepending on a free-energy barrier that Ubiquitin overcomes to translocate. Our simulations show this barrier to be the result from competition of the unfolding energy and the entropy associated to the confinement effects of the pore.

scholarly journals Computer simulation of knotted proteins unfold and translocation through nano-pores

2018 ◽  
Author(s):  
M. A. Shahzad
Keyword(s):  
Computer Simulation ◽  
Computational Model ◽  
Coarse Grained ◽  
Kinetic Properties ◽  
Constant Force ◽  
Translocation Mechanism ◽  
Translocation Time ◽  
Knotted Protein ◽  
Knotted Proteins ◽  
Pulling Force

We study the unfold and translocation of knotted protein, YibK and YbeA, through α-hemolysin nano-pore via a coarse grained computational model. We observe that knot of protein unfold in advance before the translocation take place. We also characterized the translocation mechanism by studying the thermodynamical and kinetic properties of the process. In particular, we study the average of translocation time, and the translocation probability as a function of pulling force F acting in the channel. In limit of low pulling inward constant force acting along the axis of the pore, the YibK knotted protein takes longer average translocation time as compare to YbeA knotted protein.

scholarly journals Polymer translocation through nano-pores: influence of pore and polymer deformation

2018 ◽  
Author(s):  
M. A. Shahzad
Keyword(s):  
Thermal Fluctuations ◽  
Coarse Grained ◽  
Free Energy Barrier ◽  
Transport Dynamics ◽  
Polymer Deformation ◽  
Cellular Environment ◽  
Small Pore ◽  
Drastic Increase ◽  
Translocation Time ◽  
Polymer Translocation

We have simulated polymer translocation across the a α-hemolysin nano-pore via a coarse grained computational model for both the polymer and the pore. We simulate the translocation process by allowing the protein cross a free-energy barrier from a metastable state, in the presence of thermal fluctuations. The deformation in the channel, which we model by making the radius of pore change from large to small size, can be originated by the random and non-random (systematic) cellular environment, drive out the polymer out of equilibrium during the transport dynamics. We expect that in more realistic conditions, effects originating on the translocation phenomena due to the deformability of the nano-pore can either decrease or increase the transport time of biomolecule passing through the channel. Deformation in channel can occurred because the structure of α-hemolysin channel is not completely immobile, hence a small pore deformation can be occurred during translocation process. We also discuss the effects of polymer deformation on the translocation process, which we achieve by varying the value of the empirical and dihedral potential constants. We investigate the dynamic and thermodynamical properties of the translocation process by revealing the statistics of translocation time as a function of the pulling inward force acting along the axis of the pore under the influence of small and large pore. We observed that a pore with small size can speed down the polymer translocation process, especially at the limit of small pulling force. A drastic increase in translocation time at the limit of low force for small pore clearly illustrate the strong interaction between the transport polymer and pore. Our results can be of fundamental importance for those experiments on DNA-RNA sorting and sequencing and drug delivery mechanism for anti-cancer therapy.

COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

scholarly journals Conformational and functional characterization of artificially conjugated non-canonical ubiquitin dimers

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tobias Schneider ◽  
Andrej Berg ◽  
Zeynel Ulusoy ◽  
Martin Gamerdinger ◽  
Christine Peter ◽  
...  
Keyword(s):  
Experimental Data ◽  
Functional Characterization ◽  
Isotopic Labeling ◽  
Md Simulations ◽  
Conformational Space ◽  
Coarse Grained ◽  
Covalent Attachment ◽  
Binding Studies ◽  
Polyubiquitin Chains ◽  
Polypeptide Chains

AbstractUbiquitylation is an eminent posttranslational modification referring to the covalent attachment of single ubiquitin molecules or polyubiquitin chains to a target protein dictating the fate of such labeled polypeptide chains. Here, we have biochemically produced artificially Lys11-, and Lys27-, and Lys63-linked ubiquitin dimers based on click-chemistry generating milligram quantities in high purity. We show that the artificial linkage used for the conjugation of two ubiquitin moieties represents a fully reliable surrogate of the natural isopeptide bond by acquiring highly resolved nuclear magnetic resonance (NMR) spectroscopic data including ligand binding studies. Extensive coarse grained and atomistic molecular dynamics (MD) simulations allow to extract structures representing the ensemble of domain-domain conformations used to verify the experimental data. Advantageously, this methodology does not require individual isotopic labeling of both ubiquitin moieties as NMR data have been acquired on the isotopically labeled proximal moiety and complementary MD simulations have been used to fully interpret the experimental data in terms of domain-domain conformation. This combined approach intertwining NMR spectroscopy with MD simulations makes it possible to describe the conformational space non-canonically Lys11-, and Lys27-linked ubiquitin dimers occupy in a solution averaged ensemble by taking atomically resolved information representing all residues in ubiquitin dimers into account.

scholarly journals Lessons from equilibrium statistical physics regarding the assembly of protein complexes

2019 ◽  
Vol 117 (1) ◽  
pp. 114-120 ◽  
Author(s):  
Pablo Sartori ◽  
Stanislas Leibler
Keyword(s):  
Self Assembly ◽  
Statistical Physics ◽  
Liquid Mixture ◽  
Protein Complexes ◽  
Biological Evolution ◽  
Cellular Protein ◽  
Cellular Functions ◽  
Physical Constraints ◽  
Polypeptide Chains ◽  
Protein Complex Assembly

Cellular functions are established through biological evolution, but are constrained by the laws of physics. For instance, the physics of protein folding limits the lengths of cellular polypeptide chains. Consequently, many cellular functions are carried out not by long, isolated proteins, but rather by multiprotein complexes. Protein complexes themselves do not escape physical constraints, one of the most important being the difficulty of assembling reliably in the presence of cellular noise. In order to lay the foundation for a theory of reliable protein complex assembly, we study here an equilibrium thermodynamic model of self-assembly that exhibits 4 distinct assembly behaviors: diluted protein solution, liquid mixture, “chimeric assembly,” and “multifarious assembly.” In the latter regime, different protein complexes can coexist without forming erroneous chimeric structures. We show that 2 conditions have to be fulfilled to attain this regime: 1) The composition of the complexes needs to be sufficiently heterogeneous, and 2) the use of the set of components by the complexes has to be sparse. Our analysis of publicly available databases of protein complexes indicates that cellular protein systems might have indeed evolved so as to satisfy both of these conditions.

scholarly journals Exploring the landscape of model representations

2020 ◽  
Vol 117 (39) ◽  
pp. 24061-24068 ◽  
Author(s):  
Thomas T. Foley ◽  
Katherine M. Kidder ◽  
M. Scott Shell ◽  
W. G. Noid
Keyword(s):  
Statistical Physics ◽  
Degrees Of Freedom ◽  
Large Scale ◽  
Coarse Graining ◽  
Order Parameters ◽  
Microscopic Model ◽  
Coarse Grained ◽  
Proper Order ◽  
Complex Phenomena ◽  
Protein Fluctuations

The success of any physical model critically depends upon adopting an appropriate representation for the phenomenon of interest. Unfortunately, it remains generally challenging to identify the essential degrees of freedom or, equivalently, the proper order parameters for describing complex phenomena. Here we develop a statistical physics framework for exploring and quantitatively characterizing the space of order parameters for representing physical systems. Specifically, we examine the space of low-resolution representations that correspond to particle-based coarse-grained (CG) models for a simple microscopic model of protein fluctuations. We employ Monte Carlo (MC) methods to sample this space and determine the density of states for CG representations as a function of their ability to preserve the configurational information, I, and large-scale fluctuations, Q, of the microscopic model. These two metrics are uncorrelated in high-resolution representations but become anticorrelated at lower resolutions. Moreover, our MC simulations suggest an emergent length scale for coarse-graining proteins, as well as a qualitative distinction between good and bad representations of proteins. Finally, we relate our work to recent approaches for clustering graphs and detecting communities in networks.

scholarly journals The Longitudinal Superdiffusive Motion of Block Copolymer in a Tight Nanopore

Polymers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 2931
Author(s):  
Waldemar Nowicki
Keyword(s):  
Dynamic Properties ◽  
Polymer Chains ◽  
Coarse Grained ◽  
Free Energy Barrier ◽  
Ballistic Motion ◽  
The Monte Carlo Method ◽  
Long Time ◽  
The Mean ◽  
Confined Environment ◽  
Unidirectional Motion

The structure and dynamic properties of polymer chains in a confined environment were studied by means of the Monte Carlo method. The studied chains were represented by coarse-grained models and embedded into a simple 3D cubic lattice. The chains stood for two-block linear copolymers of different energy of bead–bead interactions. Their behavior was studied in a nanotube formed by four impenetrable surfaces. The long-time unidirectional motion of the chain in the tight nanopore was found to be correlated with the orientation of both parts of the copolymer along the length of the nanopore. A possible mechanism of the anomalous diffusion was proposed on the basis of thermodynamics of the system, more precisely on the free energy barrier of the swapping of positions of both parts of the chain and the impulse of temporary forces induced by variation of the chain conformation. The mean bead and the mass center autocorrelation functions were examined. While the former function behaves classically, the latter indicates the period of time of superdiffusive motion similar to the ballistic motion with the autocorrelation function scaling with the exponent t5/3. A distribution of periods of time of chain diffusion between swapping events was found and discussed. The influence of the nanotube width and the chain length on the polymer diffusivity was studied.

scholarly journals Prion Protein Translocation Mechanism Revealed by Pulling Force Studies

2020 ◽  
Vol 432 (16) ◽  
pp. 4447-4465 ◽  
Author(s):  
Theresa Kriegler ◽  
Sven Lang ◽  
Luigi Notari ◽  
Tara Hessa
Keyword(s):  
Prion Protein ◽  
Protein Translocation ◽  
Translocation Mechanism ◽  
Pulling Force

scholarly journals Forces on nascent polypeptides during membrane insertion and translocation via the Sec translocon

2018 ◽  
Author(s):  
Michiel J.M. Niesen ◽  
Annika Müller-Lucks ◽  
Rickard Hedman ◽  
Gunnar von Heijne ◽  
Thomas F. Miller
Keyword(s):  
Conformational Changes ◽  
Protein Translocation ◽  
Translation Arrest ◽  
Protein Biogenesis ◽  
Pulling Forces ◽  
Transient Interactions ◽  
Pulling Force ◽  
Electrostatic Coupling ◽  
Polypeptide Chains ◽  
Ribosomal Translation

ABSTRACTDuring ribosomal translation, nascent polypeptide chains (NCs) undergo a variety of physical processes that determine their fate in the cell. Translation arrest peptide (AP) experiments are used to measure the external pulling forces that are exerted on the NC at different lengths during translation. To elucidate the molecular origins of these forces, a recently developed coarsegrained molecular dynamics (CGMD) is used to directly simulate the observed pulling-force profiles, thereby disentangling contributions from NC-translocon and NC-ribosome interactions, membrane partitioning, and electrostatic coupling to the membrane potential. This combination of experiment and theory reveals mechanistic features of Sec-facilitated membrane integration and protein translocation, including the interplay between transient interactions and conformational changes that occur during ribosomal translation to govern protein biogenesis.

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