Biology subjects

Reddy, G.

Publications and source records attributed to Reddy, G..

3 recordsLinked to original sources

bioRxiv2018

Receptor crosstalk improves concentration sensing of multiple ligands

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptors cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.

cell biology↗

bioRxiv2017

Antagonism in olfactory receptor neurons and its implications for the perception of odor mixtures

Natural environments feature mixtures of odorants of diverse quantities, qualities and complexities. Olfactory receptor neurons (ORNs) are the first layer in the sensory pathway and transmit the olfactory signal to higher regions of the brain. Yet, the response of ORNs to mixtures is strongly non-additive, and exhibits antagonistic interactions among odorants. Here, we model the processing of mixtures by mammalian ORNs, focusing on the role of inhibitory mechanisms. Theoretically predicted response curves capture experimentally determined glomerular responses imaged by a calcium indicator expressed in ORNs of live, breathing mice. Antagonism leads to an effective \"normalization\" of the ensemble glomerular response, which arises from a novel mechanism involving the distinct statistical properties of receptor binding and activation, without any recurrent neuronal circuitry. Normalization allows our encoding model to outperform noninteracting models in odor discrimination tasks, and to explain several psychophysical experiments in humans.

neuroscience↗

bioRxiv2016

Collapse Precedes Folding in Denaturant-Dependent Assembly of Ubiquitin

Despite the small size the folding of Ubiquitin (Ub), which plays an indispensable role in targeting proteins for degradation and DNA damage response, is complex. A number of experiments on Ub folding have reached differing conclusions regarding the relation between collapse and folding, and whether intermediates are populated. In order to resolve these vexing issues, we elucidate the denaturant-dependent thermodynamics and kinetics of Ub folding in low and neutral pH as a function of Guanidinium chloride and Urea using coarse-grained molecular simulations. The changes in the fraction of the folded Ub, and the radius of gyration (Rg) as a function of the denaturant concentration, [C], are in quantitative agreement with experiments. Under conditions used in experiments, Rg of the unfolded state at neutral pH changes only by {approx} 17% as the [GdmCl] decreases from 6 M to 0 M. We predict that the extent of compaction of the unfolded state increases as temperature decreases. A two-dimensional folding landscape as a function of Rg and a measure of similarity to the folded state reveals unambiguously that the native state assembly is preceded by collapse, as discovered in fast mixing experiments on several proteins. Analyses of the folding trajectories, under mildly denaturing conditions ([GdmCl]=1.0M or [Urea]=1.0M), shows that Ub folds by collision between preformed secondary structural elements involving kinetic intermediates that are primarily stabilized by long-range contacts. Our work explains the results of Small Angle X-Ray Scattering (SAXS) experiments on Ub quantitatively, and establishes that evolved globular proteins are poised to collapse. In the process, we explain the discrepancy between SAXS and single molecule fluorescent resonant energy transfer (smFRET) experiments, which have arrived at a contradicting conclusion concerning the collapse of polypeptide chains.

biophysics↗