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Reddy, G.

Publications and source records attributed to Reddy, G..

At least 37 records · Page 2Linked to original sources

Reinforcement waves as a mechanism for discontinuous learning

Problem-solving and reasoning involve mental exploration and navigation in sparse relational spaces. A physical analogue is spatial navigation in structured environments such as a network of burrows. Recent experiments with mice navigating a labyrinth show a sharp discontinuity during learning, corresponding to a distinct moment of sudden insight when mice figure out long, direct paths to the goal. This discontinuity is seemingly at odds with reinforcement learning (RL), which involves a gradual build-up of a value signal during learning. Here, we show that biologically-plausible RL rules combined with persistent exploration generically exhibit discontinuous learning. In tree-like structured environments, positive feedback from learning on behavior generates a reinforcement wave with a steep profile. The discontinuity occurs when the wave reaches the starting point. By examining the nonlinear dynamics of reinforcement propagation, we establish a quantitative relationship between the learning rule, the agents exploration biases and learning speed. Predictions explain existing data and motivate specific experiments to isolate the phenomenon. Additionally, we characterize the exact learning dynamics of various RL rules for a complex sequential task.

animal behavior and cognition↗

Salt Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins

Salts modulate the behavior of intrinsically disordered proteins (IDPs). In low ionic strength solutions, IDP conformations are primarily perturbed by the screening of electrostatic interactions, independent of the identity of the salt. In this regime, insight into the IDP behavior can be obtained using the theory for salt-induced transitions in charged polymers. However, in high ionic strength solutions, salt-specific interactions with the charged and uncharged residues, known as the Hofmeister effect, influence IDP behavior. There is a lack of reliable theoretical models in high salt concentration regimes to predict the salt effect on IDPs. Using a coarse-grained simulation model for the IDPs and experimentally measured water to salt solution transfer free-energies of various chemical groups, we studied the salt-specific transitions induced in the IDPs conformational ensemble. We probed the effect of three different salts, ranging from protective osmolyte to denaturant, on five IDPs belonging to various polymer classes classified based on charge content. The transitions observed in the IDP conformational ensembles are dependent on the salt used and the IDP polymer class. An important implication of these results is that a suitable salt can be identified to induce condensation of an IDP through liquid-liquid phase separation.

biophysics↗

Alternation emerges as a multi-modal strategy for turbulent odor navigation

Foraging mammals exhibit a familiar yet poorly characterized phenomenon, "alternation", a momentary pause to sniff in the air often preceded by the animal rearing on its hind legs or raising its head. Intriguingly, rodents executing an olfactory search task spontaneously exhibit alternation in the presence of airflow, suggesting that alternation may serve an important role during turbulent plume-tracking. To test this hypothesis, we combine fully-resolved numerical simulations of turbulent odor transport and Bellman optimization methods for decision-making under partial observability. We show that an agent trained to minimize search time in a realistic odor plume exhibits extensive alternation together with the characteristic cast-and-surge behavior commonly observed in flying insects. Alternation is tightly linked with casting and occurs more frequently when the agent is far downwind of the source, where the likelihood of detecting airborne cues is higher relative to cues close to the ground. Casting and alternation emerge as complementary tools for effective exploration when cues are sparse. We develop a model based on marginal value theory to capture the interplay between casting, surging and alternation. More generally, we show how multiple sensorimotor modalities can be fruitfully integrated during complex goal-directed behavior.

animal behavior and cognition↗

Riboswitch Folds to Holo-Form Like Structure Even in the Absence of Cognate Ligand at High Mg2+ Concentration

Riboswitches are non-coding RNA that regulate gene expression by folding into specific three-dimensional structures (holo-form) upon binding by their cognate ligand in the presence of Mg2+. Riboswitch functioning is also hypothesized to be under kinetic control requiring large cognate ligand concentrations. We ask the question under thermodynamic conditions, can the riboswitches populate holo-form like structures in the absence of their cognate ligands only in the presence of Mg2+. We addressed this question using thiamine pyrophosphate (TPP) riboswitch as a model system and computer simulations using a coarse-grained model for RNA. The folding free energy surface (FES) shows that with the initial increase in Mg2+ concentration ([Mg2+]), TPP AD undergoes a barrierless collapse in its dimensions. On further increase in [Mg2+], intermediates separated by barriers appear on the FES, and one of the intermediates has a TPP ligand-binding competent structure. We show that site-specific binding of the Mg2+ aids in the formation of tertiary contacts. For [Mg2+] greater than physiological concentration, AD folds into its holo-form like structure even in the absence of the TPP ligand. The folding kinetics shows that it populates an intermediate due to the misalignment of the two arms in the TPP AD, which acts as a kinetic trap leading to larger folding timescales. The predictions of the intermediate structures from the simulations are amenable for experimental verification.

biophysics↗

Energy Landscape of Ubiquitin is Weakly Multidimensional

Single molecule pulling experiments report time-dependent changes in the extension (X) of a biomolecule as a function of the applied force (f). By fitting the data to one-dimensional analytical models of the energy landscape, the hopping rates between the folded and unfolded states in two-state folders, the height and the location of the transition state (TS) can be extracted. Although this approach is remarkably insightful, there are cases for which the energy landscape is multidimensional (catch bonds being the most prominent). To assess if the unfolding energy landscape in small single domain proteins could be one dimensional, we simulated force-induced unfolding of Ubiquitin (Ub) using the coarse-grained Self-Organized Polymer-Side Chain (SOP-SC) model. Brownian dynamics simulations using the SOP-SC model reveal that the Ub energy landscape is weakly multidimensional (WMD) governed predominantly by a single barrier. The unfolding pathway is confined to a narrow reaction pathway that could be described as diffusion in a quasi 1D X-dependent free energy profile. However, a granular analysis using the Pfold analysis, which does not assume any form for the reaction coordinate, shows that X alone does not account for the height, and more importantly, the location of the TS. The f-dependent TS location moves towards the folded state as f increases, in accord with the Hammond postulate. Our study shows that, in addition to analyzing the f-dependent hopping rates, the transition state ensemble must also be determined without resorting to X as a reaction coordinate in order to describe the unfolding energy landscapes of single domain proteins, especially if they are only WMD. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/437368v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1fd1480org.highwire.dtl.DTLVardef@4d12c8org.highwire.dtl.DTLVardef@c4839org.highwire.dtl.DTLVardef@59aab9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

Sector search strategies for odor trail tracking

Terrestrial animals such as ants, mice and dogs often use surface-bound scent trails to establish navigation routes or to find food and mates, yet their tracking strategies are poorly understood. Tracking behavior features zig-zagging paths with animals often staying in close contact with the trail. Upon sustained loss of contact, animals execute a characteristic sequence of sweeping "casts" - wide oscillations with increasing amplitude. Here, we provide a unified description of trail-tracking behavior by introducing an optimization framework where animals search in the angular sector defined by their estimate of the trails heading and its uncertainty. In silico experiments using reinforcement learning based on this hypothesis recapitulate experimentally observed tracking patterns. We show that search geometry imposes limits on the tracking speed, and quantify its dependence on trail statistics and memory of past contacts. By formulating trail-tracking as a Bellman-type sequential optimization problem, we quantify the basic geometric elements of optimal sector search strategy, effectively explaining why and when casting is necessary. We propose a set of experiments to infer how tracking animals acquire, integrate and respond to past information on the tracked trail. More generally, we define navigational strategies relevant for animals and bio-mimetic robots, and formulate trail-tracking as a novel behavioral paradigm for learning, memory and planning.

animal behavior and cognition↗

Asymmetry in Histone Rotation in Forced Unwrapping and Force Quench Rewrapping in a Nucleosome

Nucleosomes, the building blocks of chromosomes, are also transcription regulators. Single molecule pulling experiments have shown that nucleosomes unwrap in two major stages, releasing nearly equal length of DNA in each stage. The first stage, attributed to the rupture of the outer turn is reversible, occurs at low forces ({approx} (3 - 5) pNs) whereas in the second stage the inner turn ruptures irreversibly at high forces (between {approx} (9 - 15) or higher) pNs. We show that Brownian dynamics simulations using the Self-Organized Polymer model of the nucleosome capture the experimental findings, thus permitting us to discern the molecular details of the structural changes not only in DNA but also in the Histone Protein Core (HPC). Upon unwrapping of the outer turn, which is independent of the pulling direction, there is a transition from 1.6 turns to 1.0 turn DNA wound around the HPC. In contrast, the rupture of the inner turn, leading to less than 0.5 turn DNA around the HPC, depends on the pulling direction, and is controlled by energetic and kinetic barriers. The latter arises because the mechanical force has to produce sufficient torque to rotate (in an almost directed manner) the HPC by 180{degrees}. In contrast, during the rewrapping process, HPC rotation is stochastic, with the quenched force fQ playing no role. Interestingly, if fQ = 0 the HPC rotation is not required for rewrapping because the DNA ends are unconstrained. The assembly of the outer wrap upon force quench, as assessed by the decrease in the end-to-end distance (Ree) of the DNA, nearly coincides with the increase in Ree as force is increased, confirming the reversible nature of the 1.6 turns to 1.0 turn transition. The asymmetry in HPC rotation during unwrapping and rewrapping accounts for the observed hysteresis in the stretch-release cycles in single molecule pulling experiments. Experiments that could validate the prediction that HPC rotation, which gives rise to the kinetic barrier in the unwrapping process, are proposed.

biophysics↗

A lexical approach for identifying behavioral action sequences

Animals display characteristic behavioral patterns when performing a task, such as the spiraling of a soaring bird or the surge-and-cast of a male moth searching for a female. Identifying such recurring sequences occurring rarely in noisy behavioral data is key to understanding the behavioral response to a distributed stimulus in unrestrained animals. Existing models seek to describe the dynamics of behavior or segment individual locomotor episodes rather than to identify the rare and transient sequences of locomotor episodes that make up the behavioral response. To fill this gap, we develop a lexical, hierarchical model of behavior. We designed an unsupervised algorithm called "BASS" to efficiently identify and segment recurring behavioral action sequences transiently occurring in long behavioral recordings. When applied to navigating larval zebrafish, BASS extracts a dictionary of remarkably long, non-Markovian sequences consisting of repeats and mixtures of slow forward and turn bouts. Applied to a novel chemotaxis assay, BASS uncovers chemotactic strategies deployed by zebrafish to avoid aversive cues consisting of sequences of fast large-angle turns and burst swims. In a simulated dataset of soaring gliders climbing thermals, BASS finds the spiraling patterns characteristic of soaring behavior. In both cases, BASS succeeds in identifying rare action sequences in the behavior deployed by freely moving animals. BASS can be easily incorporated into the pipelines of existing behavioral analyses across diverse species, and even more broadly used as a generic algorithm for pattern recognition in low-dimensional sequential data.

animal behavior and cognition↗

Double Domain Swapping in Human γC and γD Crystallin Drives Early Stages of Aggregation

Human{gamma} D (H{gamma}D) and{gamma} C (H{gamma}C) are double domained crystallin (Crys) proteins expressed in the nucleus of the eye lens. Structural perturbations in the protein often trigger aggregation, which eventually leads to cataract. To decipher the underlying molecular mechanism, it is important to characterize the partially unfolded conformations of Crys proteins. Using coarse grained protein models and molecular dynamics simulations, we studied the role of on-pathway folding intermediates in the early stages of aggregation. The multi-dimensional free energy surface revealed at least three different folding pathways with the population of partially structured intermediates. The two dominant pathways confirm sequential folding of the N-terminal [Ntd] and the C-terminal domains [Ctd], while the third, least favored pathway involves intermediates where both the domains are partially folded. A native like intermediate (I*), featuring the folded domains and disrupted inter domain contacts, gets populated in all the three pathways. I* forms domain swapped dimers by swapping the entire Ntds and Ctds with other monomers. Population of such oligomers can explain the increased resistance to unfolding resulting in hysteresis observed in the folding experiments of H{gamma}D Crys. An ensemble of double domain swapped dimers are also formed during refolding, where intermediates consisting of partially folded Ntds and Ctds swap secondary structures with other monomers. The double domain swapping model presented in our study provides structural insights into the early events of aggregation in Crys proteins and identifies the key secondary structural swapping elements, where introducing mutations will aid in regulating the overall aggregation propensity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/210443v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@fd37e6org.highwire.dtl.DTLVardef@60e7cdorg.highwire.dtl.DTLVardef@128386org.highwire.dtl.DTLVardef@178f240_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract figure C_FIG

biochemistry↗

Global epistasis emerges from a generic model of a complex trait

Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread "microscopic" epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the mechanistic basis of this "global" epistasis remains unknown. Here we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by re-analyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread, and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity.

evolutionary biology↗

Mg2+ Sensing by an RNA Fragment: Role of Mg2+ Coordinated Water Molecules

RNA molecules selectively bind to specific metal ions to populate their functional active states making it important to understand their source of ion selectivity. In large RNA systems, metal ions interact with the RNA at multiple locations making it difficult to decipher the precise role of ions in folding. To overcome this complexity, we studied the role of different metal ions (Mg2+, Ca2+ and K+) in the folding of a small RNA hairpin motif (5'-ucCAAAga-3') using unbiased all-atom molecular dynamics simulations. The advantage in studying this small system is that it requires specific binding of a single metal ion to fold to its native state. We find that even for this small RNA, the folding free energy surface (FES) is multidimensional as different metal ions present in the solution can simultaneously facilitate folding. The FES shows that specific binding of a metal ion is indispensable for its folding. We further show that in addition to the negatively charged phosphate groups, spatial organization of electronegative nucleobase atoms drive the site specific binding of the metal ion. Even though the binding site cannot discriminate between different metal ions, RNA folds efficiently only in Mg2+ solution. We show that the rigid network of Mg2+ coordinated water molecules facilitate the formation of important interactions in the transition state. The other metal ions such as K+ and Ca2+ cannot facilitate the formation of such interactions. These results allow us to hypothesize possible metal sensing mechanisms in large metallo-riboswitches and they also provide useful insights for the design of appropriate collective variables for studying large RNA molecules using enhanced sampling methods.

biochemistry↗

Antagonistic odor interactions in olfactory sensory neurons are widespread in freely breathing mice

Odor landscapes contain complex blends of discrete molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we found widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions became stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a remarkably common feature of odor mixture encoding in olfactory sensory neurons and helps in normalizing activity to reduce saturation.

neuroscience↗

ODORANT RECEPTOR INHIBITION IS FUNDAMENTAL TO ODOR ENCODING

Most natural odors are complex mixtures of many volatile components, competing to bind odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date surprisingly little is known about how OR antagonism shapes neuronal representations in the periphery of the olfactory system. Here, we investigated its prevalence, the degree to which it disrupts OR ensemble activity, and its conservation across related ORs. Calcium imaging microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of responses to indole, a commonly occurring volatile associated with both floral and fecal odors, by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we performed single-cell transcriptomics on OSNs that exhibited specific response profiles to a diagnostic panel of odorants and identified the receptor Olfr743 which, when tested in vitro, recapitulated ex vivo responses. We screened ten ORs from the Olfr743 clade with 800 perfumery-related odorants spanning a range of chemical scaffolds and functional groups, over half of which (430) antagonized at least one of the ten ORs. Furthermore, OR activity outcomes were divergent rather than redundant, even for the most closely related paralogs. OR activity fitted a mathematical model of competitive receptor binding and suggests that normalization of OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary, we observed OR antagonism, inverse agonism and partial agonism occurring frequently and in a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information appears to occur in the olfactory epithelium prior to transmission of odor information to the olfactory bulb.

neuroscience↗

A Transient Intermediate Populated in Prion Folding Leads to Domain Swapping

Aggregation of misfolded prion proteins causes fatal neurodegenerative disorders in both humans and animals. There is an extensive effort to identify the elusive aggregation-prone conformations (N*) of prions, which are early stage precursors to aggregation. Ve studied temperature and force induced unfolding of the structured C-terminal domain of mouse (moPrP) and human prion proteins (hPrP) using molecular dynamics simulations and coarse-grained protein models. Ve find that these proteins sparsely populate intermediate states bearing the features of N* and readily undergo domain-swapped dimerization by swapping the short {beta}-strands present at the beginning of the C-terminal domain. Structure of the N* state is similar for both moPrP and hPrP, indicating a common pathogenic precursor across diferent species. Interestingly, disease-resistant hPrP (G127V) showed a drastic reduction in the population of N* state further hinting a pathogenic connection to these partially denatured conformations. This study proposes a plausible runaway domain swapping mechanism to describe the onset of prion aggregation.

biophysics↗

Zinc Solubilizing Plant Growth Promoting Microbes Produce Zinc Nanoparticles

Strains of Pseudomonas, Bacillus and Azospirillum with plant growth promoting ability were checked for their zinc solubilizing ability. Efficient zinc solubilizers were checked for their ability to produce nano-scale zinc particles. The nanoparticles from the cell-free culture filtrates obtained from these strains were characterized for particle size, Zeta potential and functional groups. Presence of Zn nanoparticles in the bacterial culture filtrate was confirmed by particle distribution and Scanning electron microscope (SEM) analysis. Most properties of nanoparticles are size dependent. Zinc nanoparticles were observed to be spherical in shape and size ranged from 52.0 to 106.0 nm. Zeta potential of the Zn nanoparticles was estimated to understand the stability of the particles. The measured zeta potentials varied from -14.5mV to +179.10 mV indicating high stability and dispersion of the zinc nanoparticles. FTIR peaks at different wave numbers depicted the role of functional groups of proteins in the biosynthesis of Zn nanoparticles. This finding opens a new area of research focusing on microbe-microbe interactions in rhizosphere and plant-microbe interactions at rhizosphere apart from biosynthesis of nanoparticles, which has major applications. To our knowledge, this is the first report of production of nanoparticles as part of nutrient mobilization by plant growth promoting rhizobacteria.

microbiology↗

Role of Disulfide Bonds and Topological Frustration in the Kinetic Partitioning of Lysozyme Folding Pathways

Disulfide bonds in proteins can strongly influence the folding pathways by constraining the conformational space. Hen egg white lysozyme has four disulfide bonds and is widely studied for its antibacterial properties. Experiments on lysozyme infer that the protein folds through a fast and a slow pathway. However, the reasons for the kinetic partitioning in the folding pathways are not completely clear. Using a coarse-grained protein model and simulations, we show that two out of the four disulfide bonds, which are present in the -domain of lysozyme, are responsible for the slow folding pathway. In this pathway, a kinetically trapped intermediate state, which is close to the native state is populated. In this state, the orientation of -helices present in the -domain are misaligned relative to each other. The protein in this state has to partially unfold by breaking down the inter-helical contacts between the misaligned helices to fold to the native state. However, the topological constraints due to the two disulfide bonds present in the -domain make the protein less flexible, and it is trapped in this conformation for hundreds of milliseconds. On disabling these disulfide bonds, we find that the kinetically trapped intermediate state and slow folding pathway disappear. Simulations mimicking the folding of protein without disulfide bonds in oxidative conditions show that the native disulfide bonds are formed as the protein folds indicating that folding guides the formation of disulfide bonds. The sequence of formation of the disulfide bonds is Cys64-Cys80 [->] Cys76-Cys94 [->] Cys30-Cys115 [->] Cys6-Cys127. Any disul-fide bond, which forms before its precursor in the sequence has to break and follow the sequence for the protein to fold. These results show that lysozyme also serves as a very good model system to probe the role of disulfide bonds and topological frustration in protein folding. The predictions from the simulations can be verified by single molecule fluorescence resonance energy transfer (FRET) or single molecule pulling experiments, which can probe heterogeneity in the folding pathways.

biophysics↗

Cosolvent Effects on the Growth of Protein Aggregates Formed by a Single Domain Globular Protein and an Intrinsically Disordered Protein

Cosolvents modulate the stability of protein conformations and exhibit contrasting effects on the kinetics of aggregation by globular proteins and intrinsically disordered proteins (IDPs). The growth of ordered protein aggregates, after the initial nucleation step is believed to proceed through a dock-lock mechanism. We have studied the effect of two denaturants (guanidinium chloride (GdmCl) and urea) and four protective osmolytes (trimethylamine N-oxide (TMAO), sucrose, sarcosine, and sorbitol) on the free energy surface (FES) of the dock-lock growth step of protein aggregation using a coarse-grained protein model and metadynamics simulations. We have used the proteins cSrc-SH3 and A{beta}9-40 as model systems representing globular proteins and IDPs, respectively. The effect of cosolvents on protein conformations is taken into account using the molecular transfer model (MTM). The computed FES shows that protective osmolytes stabilize the compact aggregates, while denaturants destabilize them for both cSrc-SH3 and A{beta}9-40. However, protective osmolytes increase the effective energy barrier for the multi-step domain swapped dimerization of cSrc-SH3, which is critical to the growth of protein aggregates by globular proteins, thus slowing down overall aggregation rate. Contrastingly, denaturants decrease the effective barrier height for cSrc-SH3 dimerization, and hence enhances the aggregation rate in globular proteins. The simulations further show that cSrc-SH3 monomers unfold before dimerization and the barrier to monomer unfolding regulates the effective rate of agrgegation. In the case of IDP, A{beta}9-40, protective osmolytes decrease and denaturants increase the effective barriers in the dock-lock mechanism of fibril growth, leading to faster and slower growth kinetics, respectively.

biochemistry↗

Universal nature of collapsibility in the context of protein folding and evolution

Theory and simulations predicted sometime ago that the sizes of unfolded states of globular proteins should decrease continuously as the denaturant concentration is shifted from a high to a low value. However, small angle X-ray scattering (SAXS) data were used to assert the opposite, while interpretation of single molecule Forster resonance energy transfer experiments (FRET) supported the theoretical predictions. The disagreement between the two experiments is the SAXS-FRET controversy. By harnessing recent advances in SAXS and FRET experiments and setting these findings in the context of a general theory and simulations, we establish that compaction of unfolded states is universal. The theory also predicts that proteins rich in {beta}-sheets are more collapsible than -helical proteins. Because the extent of compaction is small, experiments have to be accurate and their interpretations should be as model free as possible. Theory also suggests that collapsibility itself could be a physical restriction on the evolution of foldable sequences, and provides a physical basis for the origin of multi-domain proteins.

biophysics↗