73 research outputs found
Molecular Recognition as an Information Channel: The Role of Conformational Changes
Molecular recognition, which is essential in processing information in
biological systems, takes place in a crowded noisy biochemical environment and
requires the recognition of a specific target within a background of various
similar competing molecules. We consider molecular recognition as a
transmission of information via a noisy channel and use this analogy to gain
insights on the optimal, or fittest, molecular recognizer. We focus on the
optimal structural properties of the molecules such as flexibility and
conformation. We show that conformational changes upon binding, which often
occur during molecular recognition, may optimize the detection performance of
the recognizer. We thus suggest a generic design principle termed
'conformational proofreading' in which deformation enhances detection. We
evaluate the optimal flexibility of the molecular recognizer, which is
analogous to the stochasticity in a decision unit. In some scenarios, a
flexible recognizer, i.e., a stochastic decision unit, performs better than a
rigid, deterministic one. As a biological example, we discuss conformational
changes during homologous recombination, the process of genetic exchange
between two DNA strands.Comment: Keywords--Molecular information channels, molecular recognition,
conformational proofreading.
http://www.weizmann.ac.il/complex/tlusty/papers/IEEE2009b.pd
Competitive Inhibition Can Linearize Dose-Response and Generate a Linear Rectifier
SummaryMany biological responses require a dynamic range that is larger than standard bi-molecular interactions allow, yet have the ability to remain off at low input. Here, we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier—that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated
Cross-species analysis traces adaptation of Rubisco towards optimality in a low dimensional landscape
Rubisco, probably the most abundant protein in the biosphere, performs an
essential part in the process of carbon fixation through photosynthesis thus
facilitating life on earth. Despite the significant effect that Rubisco has on
the fitness of plants and other photosynthetic organisms, this enzyme is known
to have a remarkably low catalytic rate and a tendency to confuse its
substrate, carbon dioxide, with oxygen. This apparent inefficiency is puzzling
and raises questions regarding the roles of evolution versus biochemical
constraints in shaping Rubisco. Here we examine these questions by analyzing
the measured kinetic parameters of Rubisco from various organisms in various
environments. The analysis presented here suggests that the evolution of
Rubisco is confined to an effectively one-dimensional landscape, which is
manifested in simple power law correlations between its kinetic parameters.
Within this one dimensional landscape, which may represent biochemical and
structural constraints, Rubisco appears to be tuned to the intracellular
environment in which it resides such that the net photosynthesis rate is nearly
optimal. Our analysis indicates that the specificity of Rubisco is not the main
determinant of its efficiency but rather the tradeoff between the carboxylation
velocity and CO2 affinity. As a result, the presence of oxygen has only
moderate effect on the optimal performance of Rubisco, which is determined
mostly by the local CO2 concentration. Rubisco appears as an experimentally
testable example for the evolution of proteins subject both to strong selection
pressure and to biochemical constraints which strongly confine the evolutionary
plasticity to a low dimensional landscape.Comment: http://www.pnas.org/content/107/8/3475.short
http://www.ncbi.nlm.nih.gov/pubmed/20142476
http://www.weizmann.ac.il/complex/tlusty/papers/PNAS2010.pd
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Achieving global perfect homeostasis through transporter regulation
Nutrient homeostasis—the maintenance of relatively constant internal nutrient concentrations in fluctuating external environments—is essential to the survival of most organisms. Transcriptional regulation of plasma membrane transporters by internal nutrient concentrations is typically assumed to be the main mechanism by which homeostasis is achieved. While this mechanism is homeostatic we show that it does not achieve global perfect homeostasis—a condition where internal nutrient concentrations are completely independent of external nutrient concentrations for all external nutrient concentrations. We show that the criterion for global perfect homeostasis is that transporter levels must be inversely proportional to net nutrient flux into the cell and that downregulation of active transporters (activity-dependent regulation) is a simple and biologically plausible mechanism that meets this criterion. Activity-dependent transporter regulation creates a trade-off between robustness and efficiency, i.e., the system's ability to withstand perturbation in external nutrients and the transporter production rate needed to maintain homeostasis. Additionally, we show that a system that utilizes both activity-dependent transporter downregulation and regulation of transporter synthesis by internal nutrient levels can create a system that mitigates the shortcomings of each of the individual mechanisms. This analysis highlights the utility of activity-dependent regulation in achieving homeostasis and calls for a re-examination of the mechanisms of regulation of other homeostatic systems
Balancing speed and accuracy of polyclonal T cell activation: a role for extracellular feedback
Background: Extracellular feedback is an abundant module of intercellular communication networks, yet a detailed
understanding of its role is still lacking. Here, we study interactions between polyclonal activated T cells that are
mediated by IL-2 extracellular feedback as a model system.
Results: Using mathematical modeling we show that extracellular feedback can give rise to opposite outcomes:
competition or cooperation between interacting T cells, depending on their relative levels of activation.
Furthermore, the outcome of the interaction also depends on the relative timing of activation of the cells. A critical
time window exists after which a cell that has been more strongly activated nevertheless cannot exclude an inferior
competitor.
Conclusions: In a number of experimental studies of polyclonal T-cell systems, outcomes ranging from cooperation
to competition as well as time dependent competition were observed. Our model suggests that extracellular
feedback can contribute to these observed behaviors as it translates quantitative differences in T cells’ activation
strength and in their relative activation time into qualitatively different outcomes. We propose extracellular
feedback as a general mechanism that can balance speed and accuracy – choosing the most suitable responders
out of a polyclonal population under the clock of an escalating threat
Comment on "ribosome utilizes the minimum free energy changes to achieve the highest decoding rate and fidelity"
We examined [Y. Savir and T. Tlusty, Cell 153, 471 (2013)10.1016/j.cell.2013.03.032] the decoding performance of tRNA by the ribosome. For this purpose, we specified the kinetics of tRNA decoding and the corresponding energy landscape, from which we calculated the steady-state decoding rate RC. Following our work, Xie reexamined [P. Xie, Phys. Rev. E 92, 022716 (2015)10.1103/PhysRevE.92.022716] the energy landscape of tRNA decoding. His analysis relies on an alternative expression for RC, while claiming that the expression we use is missing some terms. In this Comment we rederive in detail our expression for the steady-state decoding rate RC, show they hold, explain why the alternative expression for RC is inaccurate, and discuss the underlying intuition.clos
Conformational Proofreading: The Impact of Conformational Changes on the Specificity of Molecular Recognition
To perform recognition, molecules must locate and specifically bind their targets within a noisy biochemical environment with many look-alikes. Molecular recognition processes, especially the induced-fit mechanism, are known to involve conformational changes. This raises a basic question: Does molecular recognition gain any advantage by such conformational changes? By introducing a simple statistical-mechanics approach, we study the effect of conformation and flexibility on the quality of recognition processes. Our model relates specificity to the conformation of the participant molecules and thus suggests a possible answer: Optimal specificity is achieved when the ligand is slightly off target; that is, a conformational mismatch between the ligand and its main target improves the selectivity of the process. This indicates that deformations upon binding serve as a conformational proofreading mechanism, which may be selected for via evolution
Optimal Design of a Molecular Recognizer: Molecular Recognition as a Bayesian Signal Detection Problem
Numerous biological functions-such as enzymatic catalysis, the immune response system, and the DNA-protein regulatory network-rely on the ability of molecules to specifically recognize target molecules within a large pool of similar competitors in a noisy biochemical environment. Using the basic framework of signal detection theory, we treat the molecular recognition process as a signal detection problem and examine its overall performance. Thus, we evaluate the optimal properties of a molecular recognizer in the presence of competition and noise. Our analysis reveals that the optimal design undergoes a "phase transition" as the structural properties of the molecules and interaction energies between them vary. In one phase, the recognizer should be complementary in structure to its target (like a lock and a key), while in the other, conformational changes upon binding, which often accompany molecular recognition, enhance recognition quality. Using this framework, the abundance of conformational changes may be explained as a result of increasing the fitness of the recognizer. Furthermore, this analysis may be used in future design of artificial signal processing devices based on biomolecules
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