Biology subjects

Punia, R.

Publications and source records attributed to Punia, R..

4 recordsLinked to original sources

bioRxiv2025

Structural Repertoire of HCV Broadly Neutralizing Antibodies Targeting the E2 Front Layer Supersite

Structural studies of the hepatitis C virus (HCV) E2 glycoprotein in complex with broadly neutralizing antibodies (bNAbs) have been instrumental in mapping neutralizing epitopes and guiding the rational design of immunogens. However, robust structural classification of HCV bNAbs is lacking, complicating immunogen design. The majority of HCV bNAbs recognize the E2 front layer (FRLY) supersite. Here, we developed a roadmap for the structural classification of FRLY-specific bNAbs. We discovered three distinct structural classes, each utilizing a unique binding mode to engage the FRLY supersite. HCV strains with multiple FRLY polymorphisms had a profound impact on binding and neutralization of bNAbs from distinct FRLY classes. Our findings establish the FRLY as a major antigenic supersite targeted by three bNAb classes and underscore the intrinsic structural plasticity of VH1-69-encoded HCV bNAbs.

immunology↗

bioRxiv2025

Structural, Thermodynamic, and Dynamic Descriptors for Differential Mechanism of HIF-2 Activity Modulators

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors critical for cellular adaptation to low oxygen conditions. Both enhancement and inhibition of HIF-2 activity has been shown to have a significant therapeutic relevance. We used all atom molecular dynamics (MD) simulations to elucidate the molecular mechanism for the differential effects of HIF-2 ligands on its complex with aryl hydrocarbon receptor nuclear translocator (ARNT). We find that agonists and antagonists differentially alter the binding site conformation, enthalpically strengthening or weakening the heterodimerization, respectively. These local changes were linked to conformational fluctuations of the HIF-2/ARNT complex, adding an entropic component to the effect of ligand binding on stability. Finally, we report a ligand-dependent effect on the DNA-binding bHLH domains structure and dynamics, impacting the hypoxia response element (HRE) binding. Based on these findings, we present a multiscale approach to enable high-throughput virtual screening of ligands for differential modulation of the structure, dynamics, and transcriptional activity of the HIF-2/ARNT complex. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/650354v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10d5f96org.highwire.dtl.DTLVardef@fe9c79org.highwire.dtl.DTLVardef@1d2fdaeorg.highwire.dtl.DTLVardef@10ce1cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Free energy surface and molecular characterization of slow structural transitions in lipid bilayers

The need to incorporate specific molecular-scale features for largescale structural changes in biological membranes necessitate use of a multi-scale computational approach. Here, this comprises of Langevin dynamics in a normal mode space determined from an elastic network model (ENM) representation for lipid-water Hamiltonian. All atom (AA) MD simulations are used to determine model parameters, and Langevin dynamics predictions for an extensive set of bilayer properties, such as, undulation spectra, undulation relaxation rates, dynamic structure factor, and mechanical properties are validated against the data from MD simulations and experiments. The transferability of model parameters to describe dynamics of a larger lipid bilayer and a heterogeneous membrane-protein system is assessed. The developed model is coupled to the energy landscape for membrane deformations to obtain a set of generic reaction coordinates (RCs) for pore formation in two tensionless, single lipid-type bilayers, namely, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Structure evolution is carried in an AA MD simulation wherein the generic RCs are used in a path metadynamics or an umbrella sampling simulation to investigate thermodynamics of pore formation and its molecular determinants. The transition state is characterized extensively to bring out the interplay between various bilayer motions (undulations, lateral density fluctuations, thinning, lipid tilt), lipid solvation, and lipid packing.

biophysics↗

bioRxiv2021

A linear response theory based method for prediction of large scale protein conformational changes upon ligand binding

Prediction of ligand-induced protein conformational transitions is a challenging task due to a large and rugged conformational space, and limited knowledge of probable direction(s) of structure change. These transitions can involve a large scale, global (at the level of entire protein molecule) structural change and occur on a timescale of milliseconds to seconds, rendering application of conventional molecular dynamics simulations prohibitive even for small proteins. We have developed a computational protocol to efficiently and accurately predict these ligand-induced structure transitions solely from the knowledge of protein apo structure and ligand binding site. Our method involves a series of small scale conformational change steps, where at each step linear response theory is used to predict the direction of small scale global response to ligand binding in the protein conformational space (dLRT) followed by construction of a linear combination of slow (low frequency) normal modes (calculated for the structure from the previous step) that best overlaps with dLRT. Protein structure is evolved along this direction using molecular dynamics with excited normal modes (MDeNM) wherein excitation energy along each normal mode is determined by excitation temperature, mode frequency, and its overlap with dLRT. We show that excitation temperature ({Delta}T) is a very important parameter that allows limiting the extent of structural change in any one step and develop a protocol for automated determination of its optimal value at each step. We have tested our protocol for three protein-ligand systems, namely, adenylate Kinase - di(adenosine-5)pentaphosphate, ribose binding protein - {beta}-D-ribopyranose, and DNA {beta}-glucosyltransferase - uridine-5-diphosphate, that incorporate important differences in type and range of structural changes upon ligand binding. We obtain very accurate prediction for not only the structure of final protein-ligand complex (holo-structure) having a large scale conformational change, but also for biologically relevant intermediates between the apo and the holo structures. Moreover, most relevant set of normal modes for conformational change at each step are an output from our method, which can be used as collective variables for determination of free energy barriers and transition timescales along the identified pathway.

biophysics↗