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Exploring proteins multi-funnel energy landscape

An all-atom model of proteins is used to show that the same sequence of amino acids can have many alternative structures, that are very distant from, and that can be as stable as, the corresponding native structure. Such alternative structures are not easily rationalized as belonging to the native basin and indicate instead that the free energy landscape of proteins is multi-funnel-shaped and that Anfinsen's thermodynamic hypothesis alone cannot explain protein folding. An alternative two-step process for folding is proposed and its consistency with the experimental evidence available is discussed.

physics.bio-ph↗

Diffusion-limited unbinding of small peptides from PDZ domains

PDZ domains are typical examples of binding motifs mediating the formation of protein-protein assemblies in many different cells. A quantitative characterization of the mechanisms intertwining structure, chemistry and dynamics with the PDZ function represent a challenge in molecular biology. Here we investigated the influence of native state topology on the thermodynamics and the dissociation kinetics for a complex PDZ-peptide via Molecular Dynamics simulations based on a coarse-grained description of PDZ domains. Our native-centric approach neglects chemical details but incorporates the basic structural information to reproduce the protein functional dynamics as it couples to the binding. We found that at physiological temperatures the unbinding of a peptide from the PDZ domain becomes increasingly diffusive rather than thermally activated, as a consequence of the significant reduction of the free energy barrier with temperature. In turn, this results in a significant slowing down of the process of two orders of magnitude with respect to the conventional Arrhenius extrapolation from low temperature calculations. Finally, a detailed analysis of a typical unbinding event based on the rupture times of single peptide-PDZ contacts allows to shed further light on the dissociation mechanism and to elaborate a coherent picture of the relation between function and dynamics in PDZ domains.

physics.bio-ph↗

Updating Probabilities: A Complex Agent Based Example

It has been shown that one can accommodate data (Bayes) and constraints (MaxEnt) in one method, the method of Maximum (relative) Entropy (ME) (Giffin 2007). In this paper we show a complex agent based example of inference with two different forms of information; moments and data. In this example, several agents each receive partial information about a system in the form of data. In addition, each agent agrees or is informed that there are certain global constraints on the system that are always true. The agents are then asked to make inferences about the entire system. The system becomes more complex as we add agents and allow them to share information. This system can have a geometrical form, such as a crystal structure. The shape may dictate how the agents are able to share information, such as sharing with nearest neighbors. This method can be used to model many systems where the agents or cells have local or partial information but must adhere to some global rules. This could also illustrate how the agents evolve and could illuminate emergent behavior of the system.

stat.ME↗

Transient and Equilibrium Synchronization in Complex Neuronal Networks

Transient and equilibrium synchronizations in complex neuronal networks as a consequence of dynamics induced by having sources placed at specific neurons are investigated. The basic integrate-and-fire neuron is adopted, and the dynamics is estimated computationally so as to obtain the activation at each node along each instant of time. In the transient case, the dynamics is implemented so as to conserve the total activation entering the system. In our equilibrium investigations, the internally stored activation is limited to the value of the respective threshold. The synchronization of the activation of the network is then quantified in terms of its normalized entropy. The equilibrium investigations involve the application of a number of complementary characterization methods, including spectra and Principal Component Analysis, as well as of an equivalent model capable of reproducing both the transient and equilibrium dynamics. The potential of such concepts and measurements is explored with respect to several theoretical models, as well as for the neuronal network of \emph{C. elegans}. A series of interesting results are obtained and discussed, including the fact that all models led to a transient period of synchronization, whose specific features depend on the topological structures of the networks. The investigations of the equilibrium dynamics revealed a series of remarkable insights, including the relationship between spiking oscillations and the hierarchical structure of the networks and the identification of twin correlation patterns between node degree and total activation, implying that hubs of connectivity are also hubs of integrate-and-fire activation.

q-bio.NC↗

Perturbation waves in proteins and protein networks: Applications of percolation and game theories in signaling and drug design

The network paradigm is increasingly used to describe the dynamics of complex systems. Here we review the current results and propose future development areas in the assessment of perturbation waves, i.e. propagating structural changes in amino acid networks building individual protein molecules and in protein-protein interaction networks (interactomes). We assess the possibilities and critically review the initial attempts for the application of game theory to the often rather complicated process, when two protein molecules approach each other, mutually adjust their conformations via multiple communication steps and finally, bind to each other. We also summarize available data on the application of percolation theory for the prediction of amino acid network- and interactome-dynamics. Furthermore, we give an overview of the dissection of signals and noise in the cellular context of various perturbations. Finally, we propose possible applications of the reviewed methodologies in drug design.

q-bio.MN↗

Interference Effects in the Brain

Interference effects are the most spectacular manifestation of the wave nature of phenomena. This note proposes a systematic search for such effects in the brain.

physics.gen-ph↗

A singular perturbation approach to the steady-state 1D Poisson-Nernst-Planck modeling

The reduced 1D Poisson-Nernst-Planck (PNP) model of artificial nanopores in the presence of a permanent charge on the channel wall is studied. More specifically, we consider the limit where the channel length exceed much the Debye screening length and channel's charge is sufficiently small. Ion transport is described by the nonequillibrium steady-state solution of the PNP system within a singular perturbation treatment. The quantities, 1/lambda -- the ratio of the Debye length to a characteristic length scale and epsilon -- the scaled intrinsic charge density, serve as the singular and the regular perturbation parameters, respectively. The role of the boundary conditions is discussed. A comparison between numerics and the analytical results of the singular perturbation theory is presented.

physics.chem-ph↗

X-Ray Powder Diffraction from Sub-Micron Crystals of Photosystem-1 Membrane Protein

We demonstrate that powder diffraction data can be collected from sub-micron crystals of a mbrane protein with nearly two orders of magnitude more atoms than the molecules commonly used for powder diffraction. The crystals of photosystem-1 protein were size-selected using a 500 nm pore- size filter and delivered to a soft x-ray beam with a photon energy of 1.5 keV using a dynamically focused micro-jet developed for the serial crystallography experiment at beamline 9.0.1. The 10-micron jet places many such randomly oriented crystals in the x-ray beam simultaneously resulting in a powder diffraction pattern which extends to 28 angstrom resolution with just 200 seconds of x-ray exposure. The use of the jet for particle delivery allows for a thin sample, appropriate for the soft x-rays used, and continuously refreshes the crystals so that radiation damage is not possible. The small size of the crystals requires the use of lower energy photons for increased scattering strength and increased spacing between powder rings. The powder patterns obtained in this way, from abundant nano-crystals, could be used to provide low resolution molecular envelopes if phased using techniques such as compressive sensing which do not require atomic resolution data. The results also serve to test our aerojet injector system, with future application to femtosecond diffraction in Free Electron X-ray Laser schemes, and for Serial Crystallography using a single-file beam of aligned hydrated molecules.

physics.bio-ph↗

Quantum Zeno Effect in Radical-Ion-Pair Recombination Reactions

Radical-ion pairs are ubiquitous in a wide range of biochemical reactions, ranging from photosynthesis to magnetic sensitive chemical reactions underlying avian magnetic navigation. We here show that the charge recombination of a radical-ion-pair is a continuous quantum measurement process that interrogates the spin state of the pair. This naturally leads to the appearance of the quantum Zeno effect, explaining a large amount of data on unusually long-lived radical-ion-pairs.

quant-ph↗

Quantum Theory of Radical-Ion-Pair Recombination: A New Physical Paradigm for Low-Magnetic-Field Effects

A new paradigm emerging in the description of magnetic-sensitive radical-ion-pair recombination reactions is presented. This paradigm is founded on the realization that the recombination process of radical-ion pairs is a continuous quantum measurement. In the regime of low magnetic fields we describe the appearance of purely quantum phenomena, that fade away as the magnetic field increases. We will analyze the magnetic sensitivity of these reactions under this perspective and bridge the new full quantum theory with the existing classical reaction theory applicable at high magnetic fields. Based on the quantum theory of recombination we will then explain experimental observations incompatible with classical reaction theory, in particular the effect of deuteration on the magnetic sensitivity of radical-ion pair recombination yields.

quant-ph↗

Osmotic pressure: resisting or promoting DNA ejection from phage

Recent in vitro experiments have shown that DNA ejection from bacteriophage can be partially stopped by surrounding osmotic pressure when ejected DNA is digested by DNase I on the course of ejection. We argue in this work by combination of experimental techniques (osmotic suppression without DNaseI monitored by UV absorbance, pulse-field electrophoresis, and cryo-EM visualization) and simple scaling modeling that intact genome (i.e. undigested) ejection in a crowded environment is, on the contrary, enhanced or eventually complete with the help of a pulling force resulting from DNA condensation induced by the osmotic stress itself. This demonstrates that in vivo, the osmotically stressed cell cytoplasm will promote phage DNA ejection rather than resisting it. The further addition of DNA-binding proteins under crowding conditions is shown to enhance the extent of ejection. We also found some optimal crowding conditions for which DNA content remaining in the capsid upon ejection is maximum, which correlates well with the optimal conditions of maximum DNA packaging efficiency into viral capsids observed almost 20 years ago. Biological consequences of this finding are discussed.

physics.bio-ph↗

Atomic Biology, Electrostatics, and Ionic Channels

I believe an atomic biology is needed to supplement present day molecular biology, if we are to design and understand proteins, as well as define, make, and use them. Topics in the paper are molecular biology and atomic biology. Electrodiffusion in the open channel. Electrodiffusion in mixed electrolytes. Models of permeation. State Models of Permeation are Inconsistent with the Electric Field. Making models in atomic biology. Molecular dynamics. Temporal Limitations; Spatial Limitations; Periodic boundary conditions. Hierarchy of models of the open channel. Stochastic Motion of the Channel. Langevin Dynamics. Simulations of the Reaction Path: the Permion. Chemical reactions. What was wrong? Back to the hierarchy: Occam's razor can slit your throat. Poisson-Nernst-Planck PNP Models Flux Ratios; Pumping by Field Coupling. Gating in channels of one conformation. Gating by Field Switching; Gating Current; Gating in Branched Channels; Blocking. Back to the hierarchy: Linking levels. Is there a theory? At what level will the adaptation be found? Simplicity, evolution, and natural function.

q-bio.BM↗

Permeation as a Diffusion Process

The paper shows how the diffusive movement of ions through a channel protein can be described as a chemical reaction over an arbitrary shaped potential barrier. The result is simple and intuitive but without approximation beyond the electrodiffusion description of ion movement.

q-bio.BM↗

Cooperation Evolution in Random Multiplicative Environments

Most real life systems have a random component: the multitude of endogenous and exogenous factors influencing them result in stochastic fluctuations of the parameters determining their dynamics. These empirical systems are in many cases subject to noise of multiplicative nature. The special properties of multiplicative noise as opposed to additive noise have been noticed for a long while. Even though apparently and formally the difference between free additive vs. multiplicative random walks consists in just a move from normal to log-normal distributions, in practice the implications are much more far reaching. While in an additive context the emergence and survival of cooperation requires special conditions (especially some level of reward, punishment, reciprocity), we find that in the multiplicative random context the emergence of cooperation is much more natural and effective. We study the various implications of this observation and its applications in various contexts.

q-fin.GN↗

Geometrical Bioelectrodynamics

This paper proposes rigorous geometrical treatment of bioelectrodynamics, underpinning two fast-growing biomedical research fields: bioelectromagnetism, which deals with the ability of life to produce its own electromagnetism, and bioelectromagnetics, which deals with the effect on life from external electromagnetism. Keywords: Bioelectrodynamics, exterior geometrical machinery, Dirac-Feynman quantum electrodynamics, functional electrical stimulation

q-bio.QM↗

Elasticity of Spider dragline Silks Viewed as Nematics: Yielding Induced by Isotropic-Nematic Phase Transition

Spider dragline silk shows well-known outstanding mechanical properties. However, its sigmoidal shape of the measured stress-strain curves (i.e. the yield) can not be described by classical polymer theories and recent hierarchical chain model. To solve the long lasting problem, we generalized the Maier-Saupe theory of nematics to construct an elastic model for the polypeptide chain network of the dragline silk. The comprehensive agreement between theory and experiments on the stress-strain curve strongly indicates the dragline silks to belong to liquid crystal elastomers. Especially, the remarkable yielding elasticity of the silk is understood for the first time as the force-induced isotropic-nematic phase transition of the chain network. Our theory also predicts a drop of the stress in supercontracted dragline silk, an early found effect of humidity on the mechanical property in many silks.

physics.bio-ph↗

Weighted-Interaction Nestedness Estimator (WINE): A new estimator to calculate over frequency matrices

We have developed a graphical user interface (GUI) running in Matlab, called Weighted-Interaction Nestedness Estimator, WINE (Fig. 1). WINE is a Matlab application developed to perform the calculation of the new weighted nestedness estimator. This program allows the user to: open a data file, select the range of data to be analysed, and calculate the results, obtaining two graphics and three indices. The indices shown in the graphical interface are: a) weighted nestedness of the frequency matrix, b) average weighted nestedness of 100 random matrices of similar characteristics, and c) the new weighted- interaction nestedness estimator, which compares the two previous results.

physics.bio-ph↗

Coarse-graining stochastic biochemical networks: quasi-stationary approximation and fast simulations using a stochastic path integral technique

We propose a universal approach for analysis and fast simulations of stiff stochastic biochemical kinetics networks, which rests on elimination of fast chemical species without a loss of information about mesoscopic, non-Poissonian fluctuations of the slow ones. Our approach, which is similar to the Born-Oppenheimer approximation in quantum mechanics, follows from the stochastic path integral representation of the full counting statistics of reaction events (also known as the cumulant generating function). In applications with a small number of chemical reactions, this approach produces analytical expressions for moments of chemical fluxes between slow variables. This allows for a low-dimensional, interpretable representation of the biochemical system, that can be used for coarse-grained numerical simulation schemes with a small computational complexity and yet high accuracy. As an example, we consider a chain of biochemical reactions, derive its coarse-grained description, and show that the Gillespie simulations of the original stiff system, the coarse-grained simulations, and the full analytical treatment are in an agreement, but the coarse-grained simulations are three orders of magnitude faster than the Gillespie analogue.

q-bio.MN↗