In a diffusion-based molecular communication network, transmitters and receivers communicate by using signalling molecules (or ligands) in a fluid medium. This paper assumes that the transmitter uses different chemical reactions to generate different emission patterns of signalling molecules to represent different transmission symbols, and the receiver consists of receptors. When the signalling molecules arrive at the receiver, they may react with the receptors to form ligand-receptor complexes. Our goal is to study the demodulation in this setup assuming that the transmitter and receiver are synchronised. We derive an optimal demodulator using the continuous history of the number of complexes at the receiver as the input to the demodulator. We do that by first deriving a communication model which includes the chemical reactions in the transmitter, diffusion in the transmission medium and the ligand-receptor process in the receiver. This model, which takes the form of a continuous-time Markov process, captures the noise in the receiver signal due to the stochastic nature of chemical reactions and diffusion. We then adopt a maximum a posteriori framework and use Bayesian filtering to derive the optimal demodulator. We use numerical examples to illustrate the properties of this optimal demodulator.
Others: The results of this paper may also be of interest to biologists who are interested to understand how living cells can distinguish between different concentration levels @cite_40 @cite_49 . The result of this paper can be viewed as a generalisation of @cite_40 which studies how cells can distinguish between two constant levels of ligand concentration.
@cite_40 @cite_49
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Chemotactic cells of eukaryotic organisms are able to accurately sense shallow chemical concentration gradients using cell-surface receptors. This sensing ability is remarkable as cells must be able to spatially resolve small fractional differences in the numbers of particles randomly arriving at cell-surface receptors by diffusion. An additional challenge and source of uncertainty is that particles, once bound and released, may rebind the same or a different receptor, which adds to noise without providing any new information about the environment. We recently derived the fundamental physical limits of gradient sensing using a simple spherical-cell model, but not including explicit particle-receptor kinetics. Here, we use a method based on the fluctuation-dissipation theorem (FDT) to calculate the accuracy of gradient sensing by realistic receptors. We derive analytical results for two receptors, as well as two coaxial rings of receptors, e.g. one at each cell pole. For realistic receptors, we find that particle rebinding lowers the accuracy of gradient sensing, in line with our previous results. The ability to predict the mechanisms and the associated rate constants of protein–ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin–benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k o f f is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k o n . Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical rate-limiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein–ligand systems and a valid support for drug design. Cells send and receive signals through pathways that have been defined in great detail biochemically, and it is often presumed that the signals convey only level information. Cell signaling in the presence of noise is extensively studied but only rarely is the speed required to make a decision considered. However, in the immune system, rapidly developing embryos, and cellular response to stress, fast and accurate actions are required. Statistical theory under the rubric of “exploit–explore” quantifies trade-offs between decision speed and accuracy and supplies rigorous performance bounds and algorithms that realize them. We show that common protein phosphorylation networks can implement optimal decision theory algorithms and speculate that the ubiquitous chemical modifications to receptors during signaling actually perform analog computations. We quantify performance trade-offs when the cellular system has incomplete knowledge of the data model. For the problem of sensing the time when the composition of a ligand mixture changes, we find a nonanalytic dependence on relative concentrations and specify the number of parameters needed for near-optimal performance and how to adjust them. The algorithms specify the minimal computation that has to take place on a single receptor before the information is pooled across the cell. Many crucial biological processes operate with surprisingly small numbers of molecules, and there is renewed interest in analyzing the impact of noise associated with these small numbers. Twenty-five years ago, Berg and Purcell showed that bacterial chemotaxis, where a single-celled organism must respond to small changes in concentration of chemicals outside the cell, is limited directly by molecule counting noise and that aspects of the bacteria's behavioral and computational strategies must be chosen to minimize the effects of this noise. Here, we revisit and generalize their arguments to estimate the physical limits to signaling processes within the cell and argue that recent experiments are consistent with performance approaching these limits.