Biology subjects

Sastry, S.

Publications and source records attributed to Sastry, S..

5 recordsLinked to original sources

bioRxiv2026

Gaussian accelerated Molecular Dynamics - Thermodynamic Integration (GaMD-TI): Improved alchemical free energy calculations with enhanced sampling

It is valuable to calculate alchemical free energy changes in drug discovery and development. Thermodynamics Integration (TI) has been widely used in computational chemistry for estimating free energy changes with alchemical transformations. However, TI based on usually short Molecular Dynamics (MD) simulations often suffers from insufficient conformational sampling. Here, we have integrated Gaussian accelerated MD and TI (GaMD-TI) to enhance the conformational sampling and improve accuracy of free energy calculations. GaMD-TI has been demonstrated in model systems of alchemical changes in the Valine dipeptide and mutation cycle of the Alanine <-> Valine <-> Isoleucine (AVI) residues. Simulations showed that when GaMD boost potentials followed near-Gaussian distribution, the free energy change could be reweighted accurately through generalized cumulant expansion to the second order. The total free energy change often exhibited faster convergence using Selective GaMD (SGaMD) than using conventional MD (cMD). Accuracy of the free energy estimates from SGaMD-TI simulations was similar to or higher than those from cMD-TI simulations, although the differences were subtle for these small model systems. Meanwhile, dihedral angles in the model systems underwent significantly more frequent conformational transitions in SGaMD than in cMD, indicating improved sampling. Future studies are planned on larger systems with more complicated alchemical changes, such as ligand binding to proteins/nucleic acids and mutations at biomolecular binding interfaces. GaMD-TI should be broadly applicable to alchemical free energy calculations and therapeutic design.

biochemistry↗

bioRxiv2025

Multiomics Approach to Regionally Profile Zinc-Driven Host-Gut Microbiome Interactions in the Intestinal Tract

Zinc deficiency (ZnD) is a major risk factor for metabolic and inflammatory diseases associated with gut microbial alterations, such as obesity, type 2 diabetes, and inflammatory bowel disease. Despite its importance, there are no established dietary recommendations for zinc supplementation in individuals with these conditions, except in cases of severe diarrhea in children. This gap stems from inconsistent outcomes in zinc supplementation trials, suggesting an incomplete understanding of zinc-mediated spatial and temporal regulation within the host-microbiome interface. This study employed a multiomics approach to investigate zinc-driven host-gut microbial interactions in the intestinal tract of mice fed zinc-adequate or ZnD diets. Radio tracing and metallomics analyses uncovered differential zinc abundance across intestinal tissues, with conventionalized germ-free mice displaying significantly lower zinc levels than germ-free mice, highlighting the reciprocal regulation of zinc between host tissues and gut microbes. Transcriptomic analyses revealed region-specific effects of ZnD, including altered energy metabolism and apoptosis in the small intestine, and impaired barrier function and redox processes in the colon. Metagenomics profiling revealed that ZnD reduced microbial diversity in the small intestine, while the cecum and colon were protected from diversity loss but exhibited an increased abundance of pathogenic bacteria. Correlation analyses linked tissue-specific host gene expression to shifts in microbial populations, identifying potential microbial mediators of host transcription changes under ZnD. Collectively, these findings emphasize the critical role of zinc in spatially regulating host-microbiome interactions, advancing our understanding of region-specific impacts of ZnD on the GI tract and disease risk. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/662895v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@235941org.highwire.dtl.DTLVardef@b8f1deorg.highwire.dtl.DTLVardef@f283eorg.highwire.dtl.DTLVardef@11b039a_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Protein as evolvable functionally-constrained amorphous matter

We explore current ideas around the representation of a protein as an amorphous material, in turn represented by an abstract graph [G] with edges weighted by elastic stiffnesses. By embedding this graph in physical space, we can map every graph to a spectrum of conformational fluctuations and responses (as a result of say, ligand-binding). This sets up a "genotype-phenotype" map, which we use to evolve the amorphous material to select for fitness. Using this, we study the emergence of allosteric interaction, hinge joint, crack formation and a slide bolt in functional proteins such as Adenylate kinase, HSP90, Calmodulin and GPCR proteins. We find that these emergent features are associated with specific geometries and mode spectra of floppy or liquid-like regions. Our analysis provides insight into understanding the architectural demands on a protein that enable a prescribed function and its stability to mutations.

biophysics↗

bioRxiv2020

Controlled neighbor exchanges drive glassy behavior, intermittency and cell streaming in epithelial tissues

Cell neighbor exchanges are integral to tissue rearrangements in biology, including development and repair. Often these processes occur via topological T1 transitions analogous to those observed in foams, grains and colloids. However, in contrast to in non-living materials the T1 transitions in biological tissues are rate-limited and cannot occur instantaneously due to the finite time required to remodel complex structures at cell-cell junctions. Here we study how this rate-limiting process affects the mechanics and collective behavior of cells in a tissue by introducing this important biological constraint in a theoretical vertex-based model as an intrinsic single-cell property. We report in the absence of this time constraint, the tissue undergoes a motility-driven glass transition characterized by a sharp increase in the intermittency of cell-cell rearrangements. Remarkably, this glass transition disappears as T1 transitions are temporally limited. As a unique consequence of limited rearrangements, we also find that the tissue develops spaitally correlated streams of fast and slow cells, in which the fast cells organize into stream-like patterns with leader-follower interactions, and maintain optimally stable cell-cell contacts. The predictions of this work is compared with existing in-vivo experiments in Drosophila pupal development.

biophysics↗

bioRxiv2020

A neutrophil-driven inflammatory signature characterizes the blood cell transcriptome fingerprints of Psoriasis and Kawasaki Disease

BackgroundTranscriptome profiling approaches have been widely used in the investigation of mechanisms underlying psoriasis pathogenesis. In most instances, changes in transcript abundance have been measured in skin biopsies. Fewer studies have examined changes in the blood samples from patients with psoriasis. While changes in the periphery may be less relevant, the blood cell transcriptome analysis presents the distinct advantage of being amenable to comparison across diseases. MethodsTwo public psoriasis blood transcriptome datasets were reanalyzed and compared against reference datasets encompassing 16 immune states and pathologies, employing a recently established modular repertoire framework. ResultsAlthough perturbations in psoriasis were relatively subtle in comparison to other auto-immune or auto-inflammatory diseases, consistent changes were observed for a signature associated with neutrophil activation/inflammation. This transcriptional signature most resembled that of subjects with Kawasaki disease. ConclusionsThe similarities observed between psoriasis and Kawasaki disease blood transcriptome signatures suggest that immune mechanisms driving the pathogenesis of these diseases may be at least partially shared. This notion is reinforced by case reports describing the development of psoriasis disease in patients with Kawasaki disease. Potential implications for novel therapeutic approaches, including the repurposing of biologic drugs targeting IL17 or its receptor for the treatment of Kawasaki disease are discussed.

immunology↗