Biology subjects

Maiti, P. K.

Publications and source records attributed to Maiti, P. K..

At least 19 recordsLinked to original sources

bioRxiv2026

Decoding Clade-Specific bNAb-HIV-1 Env Interactions Using Machine Learning

Human immunodeficiency virus type 1 (HIV-1) exhibits extensive genetic diversity, posing a major challenge to AIDS vaccine development. Broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals offer valuable templates for designing broadly protective immunogens. Here, structural and energetic descriptors extracted from experimentally resolved bNAb/HIV-1 Envelope (Env) protein-protein complexes were used to develop machine-learning (ML) models predicting binding free energies ({triangleup}G) and dissociation constants (KD) across multiple HIV-1 clades. Among the algorithms evaluated, extreme gradient boosting (XGBoost) achieved the best predictive performance, with training and test R2 values of 0.92 and 0.658, respectively. Applying the optimized model to HIV-1 datasets revealed clade-dependent binding patterns, with clade B showing the greatest variability and clade G exhibiting signatures associated with reduced neutralization potency. Predicted {triangleup}G of different bNAb classes followed the trend gp120-gp41 interface {approx} fusion domain > CD4 binding site (CD4bs) > V1V2 loop {approx} V3-glycan, consistent with experimentally reported affinity profiles of benchmark bNAbs. Clade C exhibited intermediate {triangleup}G with PGT121, VRC01, and 10-1074 maintaining high-affinity interactions, whereas PG9 and 2G12 show reduced binding affinity. These findings offer quantitative insight into clade-specific bNAb binding energetics and demonstrate the potential of machine-learning approaches to guide HIV-1 immunogen design and vaccine development.

biochemistry↗

bioRxiv2026

Breaking Pore Symmetry to Prolong DNA Residence in Solid-State Nanopores

Rapid DNA transport limits the temporal resolution of solid-state nanopore sensing. Here we show that breaking pore symmetry through geometric inclination produces exceptionally prolonged DNA residence without surface functionalization or external trapping. For 500-base-pair double-stranded (ds) DNA ,13 nm diameter SiNx pores in tilted membranes exhibit a distinct long-lived population with a mean dwell time of 11.1 seconds at 600 mV bias, exceeding previously reported dsDNA dwell times by at-least 4 orders of magnitude. Controlled pore tilting reproduces the population of prolonged events, whose prevalence and duration depend on ionic strength. TEM-EELS based thickness measurements exclude substantial membrane-thickness differences, while continuum and atomistic simulations support a mechanism coupling electric-field redistribution to off-axis DNA motion, increased pore-wall contact and suppressed axial mobility. These findings establish geometric inclination as a passive design variable for engineering molecular residence in solid-state nanopores and provide a route towards longer observation windows for single-molecule sensing.

bioengineering↗

bioRxiv2026

Nanopore Electrometry Resolves Peptide Charge Patterns beyond Ionic-Current Blockade

Localized measurements of electric fields offer a promising route to expand the information content of nanopore-based single-molecule sensing beyond conventional ionic-current blockade. Here, using all-atom molecular dynamics simulations with virtual electric-field probes placed around a graphene nanopore, we show that the local electric-field captures the presence, and distribution of charged amino acids as the peptides translocate through the pore. These field signatures create reproducible peptide-specific fingerprints across independent translocation events and enable substantially improved discrimination between peptides compared with ionic-current traces obtained under the same simulation conditions. Our results suggest that localized nanopore electrometry can provide a complementary, information-rich readout of peptide charge order that is largely inaccessible to conventional current blockade-based measurement. This study establishes a simulation-guided framework for integrating nanoscale electrometry with nanopore platforms for future peptide and protein analysis.

biophysics↗

bioRxiv2026

PTM-Driven Reshaping of the Peptide Translocation Landscape in Bilayer Graphene Nanopores

Post-translational modifications (PTMs) underpin much of protein regulation, yet their single-molecule readout remains a challenge in nanopore proteomics. While biological nanopores have shown exquisite PTM sensitivity, the microscopic mechanisms by which PTMs perturb signals in solid-state nanopores are largely unexplored. Here, we use all-atom molecular dynamics to investigate how three common PTMs, acetylation, phosphorylation, and methylation, modulate the translocation of a cancer-relevant p53 peptide fragment through a bilayer graphene nanopore. We find that PTMs remodel the translocation landscape far more strongly at the level of dwell-time statistics than at the level of mean current blockade. Acetylation enhances peptide-graphene adhesion and substantially slows transport, with adjacent acetylations producing the longest residence times due to cooperative interfacial interactions, while remotely spaced acetylations yield broader, heterogeneous dynamics. Phosphorylation introduces a negative charge that increases dwell time through an electrostatic tug-of-war, while also generating the largest current blockade among the PTMs studied. In contrast, methylation minimally perturbs translocation due to weak pore interactions and preserved charge. Combining dwell time with relative blockade features enables a simple linear SVM classifier to reliably distinguish unmodified, acetylated, and phosphorylated states. These results establish mechanistic design principles for PTM detection using solid-state nanopores and delineate which classes of PTMs are the most amenable to single-molecule detection with these devices.

biophysics↗

bioRxiv2025

DNA Nanocage-Mediated Aspirin Delivery Mitigates Excitotoxicity and Promotes Neuroprotection in Ischemic Stroke-Induced Zebrafish

Oxidative stress, apoptosis, excitotoxicity, and compromised neuronal function are the hallmarks of ischaemic stroke, a major cause of neurological impairment. Because of their controlled-release properties and biocompatibility, DNA tetrahedron nanostructures (TD) offer a viable platform for targeted drug delivery. In this work, we used a zebrafish larval model of ischaemic stroke to assess the neuroprotective potential of TD-mediated aspirin administration and investigated the TD:Aspirin complexation modes using molecular dynamics (MD) simulations. In addition to morphological abnormalities, elevated reactive oxygen species (ROS), thrombus formation, intracellular calcium accumulation, and dysregulated expression of neuroprotective and apoptotic genes, stroke induction resulted in significant behavioural deficits, including decreased locomotor activity, increased latency, and erratic swimming. Treatment with TD:Aspirin, especially at a 1:100 ratio, markedly improved locomotor behaviour, restored production of BDNF, GDNF, MBP, -tubulin, GRIN2B, SLC8A, NOS1, and caspases, normalised heart rate, lowered ROS generation and apoptosis, and decreased thrombus and calcium deposition. TD:Aspirin showed better efficacy than free Aspirin and TD-only groups, perhaps as a result of improved stability, bioavailability, and sustained release. These results demonstrate the potential of drug delivery via DNA nanocages as a novel therapeutic approach for ischaemic stroke, offering neuroprotection, functional recovery, and neuronal homeostasis restoration. TOC GraphicDNA Nanocage-Mediated Aspirin Delivery Mitigates Excitotoxicity and Promotes Neuroprotection in Ischemic Stroke-Induced Zebrafish O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/696221v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@18dd327org.highwire.dtl.DTLVardef@21b8b4org.highwire.dtl.DTLVardef@1e53283org.highwire.dtl.DTLVardef@5771e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

In silico self-assembly and complexation dynamics of cationic lipids with DNA nanocages to enhance lipofection

DNA nanostructures are promising materials for drug delivery due to their unique topology, shape, size control, biocompatibility, structural stability and blood-brain-barrier (BBB) penetration capability. However, their cellular permeability is hindered by strong electrostatic repulsion from negatively charged cellular membranes, posing a significant obstacle to the use of DNA nanostructures as a drug delivery vehicle. Recent experimental studies have shown enhanced cellular uptake for the conjugate binary mixtures of DNA Tetrahedron (TDN) with cationic lipid N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) compared to TDN alone. However, the cationic DOTMA lipids binding mechanism with the TDN nucleotides is still elusive. Using fully atomistic MD simulations, we aim to understand the molecular interactions that drive the formation and stability of the TDN-DOTMA binary complexes in a physiological environment. Our results uncovered that lipid concentration plays a crucial role in the energetics of the TDN-DOTMA association. We also report that distinct timescales are associated with the self-assembly of cationic DOTMA lipids first, followed by the complexation of self-assembled DOTMA lipid clusters with the TDN nucleotides, where electrostatics, hydrophobicity, and hydrogen bonding are the key interactions that drive the formation and stability of these complexes. These results provide molecular insights into TDN-DOTMA interactions, highlighting the lipid self-assembly dynamics, complex stability, and morphology, paving the way for the better rational design of cationic lipid functionalized DNA nanostructures for efficient drug delivery and transfection.

biophysics↗

bioRxiv2025

Clade-specific influences of glycans on the interactions between HIV-1 envelope and broadly neutralizing antibodies

N-linked glycans are important in the elicitation and the activity of many broadly neutralizing antibodies (bNAbs) against HIV-1. The high conformational flexibility of glycans hindered detailed atomistic investigations of glycan-bNAb interactions, including glycan shielding of bN-Abs. Importantly, how these interactions vary across different HIV-1 clades remains unclear. The variability in the number and location of potential N-linked glycosylation sites (PNGS) on the HIV-1 envelope (Env) protein across clades can lead to differences in glycan dynamics and topology, potentially affecting Env-bNAb interactions and the clade-specific efficacy of bNAb-based therapies. Here, we combined comprehensive glycan conformational sampling, using the software glycoSHIELD, and molecular dynamics (MD) simulations to model fully glycosylated trimeric Env for six HIV-1 strains, one from each of the major clades A, B, C, G, CRF01 AE (01 AE) and CRF07 BC (07 BC). We assessed the interactions of 50 different bNAbs, drawn from all the major bNAb classes, with each of these strains, quantifying glycan shielding, glycan-bNAb interactions, and their clade-specific variations for each bNAb in microscopic detail. Our findings reveal that while glycans cover most of the exposed surface area in all clades, the amount of accessible surface varies, with clade B having the minimum and clade 07 BC the maximum antibody accessible surface area. The number of glycan conformers per glycosylation site also varies with clades, even for conserved sites. Overall, we observed that bNAbs interact with more glycans than previously reported in experimental and computational studies. Important variations emerge in Env-bNAb interactions with clade and bNAb-class. These atomic-level insights will be valuable for improving bNAb-based therapies and vaccine design strategies against HIV-1. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/655089v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@eedc04org.highwire.dtl.DTLVardef@1aebf67org.highwire.dtl.DTLVardef@1982a02org.highwire.dtl.DTLVardef@ee08e5_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Mechanistic Insights into Crossover-Dependent Stability and Exceptional Resistance of PX/JX Nanostructures to DNase I using Enhanced Sampling

Designing biostable DNA nanocarriers for precise therapeutic delivery remains a key challenge in DNA nanotechnology due to susceptibility to nuclease degradation. Multi-stranded DNA nanostructures, such as Paranemic crossover (PX) DNA, show enhanced biostability compared to native duplex DNA due to their unique topology. However, the molecular origin of their exceptional nuclease resistance is still unknown. Using atomistic MD simulation and enhanced sampling, we uncover the molecular origins of PX-DNAs superior resistance over JX-DNA and dsDNA. Our findings reveal that PX-DNAs six crossover points induce an overtwisted helix and narrower minor groove, leading to reduced DNase I binding affinity ([~] +5 kcal/mol for PX-DNA vs. [~] -17 kcal/mol for dsDNA). Mechanical properties, such as the stretch modulus ({gamma}G), confirm enhanced structural rigidity of PX-DNA (4805 pN), while residence time calculations using{tau} -RAMD further highlight shorter residence time of DNase I nuclease on PX-DNA. This is the first theoretical study to explore crossover-dependent biostability, mechanical properties, and residence time of PX/JX nanostructures in the presence of a nuclease using enhanced sampling. Our findings highlight that strategically positioned crossover points can regulate DNA stability against nuclease degradation at the nanoscale and lead to better design of biostable DNA nanostructures for medicinal applications.

biophysics↗

bioRxiv2025

AT vs. GC binding of protamine-template: A microscopic understanding through molecular dynamics and binding free energies

Protamine, an arginine-rich protein, compacts DNA more tightly than histones in somatic cells, yet its sequence-specific binding remains unclear. Using all-atom MD simulations with an arginine-rich short cationic peptide that mimics the protamine characteristics, we discovered distinct sequence preferences: the peptide binds preferentially to GC-rich sequences in the major groove and AT-rich sequences in the minor groove. Our structural analysis reveals that GC-rich binding induces significant DNA bending, narrowing the major groove and enhancing peptide interactions. In contrast, AT-rich minor grooves are more extended and electronegative, allowing better stereochemical fitting with planar and aromatic guanidinium side groups of arginine. However, thymines methyl group hinders major groove binding, favoring guanine. Thermodynamic free energy calculations, including MMGBSA, Jarzynskis Equality, and Umbrella Sampling, confirm stronger peptide affinity for AT-rich motifs in the minor groove and GC-rich motifs in the major groove. Overall, this study will contribute to enhancing our understanding of DNA condensation and compaction in sperm cells based on protamines sequence-specific interactions.

biophysics↗

bioRxiv2025

Orientation Dependence of Current Blockade in Single Amino Acid Translocation through a Graphene Nanopore

After successful commercialization of DNA sequencing with biological nanopores, the next frontier of the nanopore technology is protein sequencing which is far more daunting a task. Molecules passing through solid-state nanopores produce current blockades that correlate with their volume linearly in the simplest conceivable model. As thinner membranes provide better volume sensitivity, 2D materials such as Graphene, MoS2 membranes have been explored. Molecular dynamics studies, mostly of homogeneous polypeptide chains translocating through 2D membranes, have been reported. In this paper, we study the translocation of all the twenty single amino acids through monolayer and bilayer graphene nanopores using all-atom molecular dynamics. These studies were motivated by the fact that single amino-acids being the building blocks of peptide chains, can help us understand pore-molecule interactions during translocations at a more basic level, for instance, avoiding neighbor effects present in a chain. We show here that the correlation between the ionic current blockade and the volume of single amino acids is strongly affected by their orientation at the pore, especially when the molecule is static at pore. We explain this phenomenon by the fact that with increasing vdW volume, the amino acid in a particular orientation, has longer projection along the perpendicular direction of the pore plane. We demonstrate distinctive current and force signals for different amino-acid translocation. We observe that some of the smaller amino acids with low molecular volume produce disproportionately high current blockades in a particular orientation due to their low structural fluctuations during translocation. We investigate how dipole-moment (of the translocating amino-acids) and its alignment with electric field in the pore can be linked with our observations.

biophysics↗

bioRxiv2025

siRNA complexation with Galactose-Functionalized Dendrimer: PAMAM vs PETIM

siRNA-based therapies hold promise for treating various diseases, but efficient and targeted delivery remains challenging. This study explored the potential of galactose-functionalized poly(amidoamine) (Gal-PAMAM) and poly(propyl ether amine) (Gal-PETIM) dendrimers as siRNA carriers using all-atom molecular dynamics simulations. This study revealed distinct complexation behavior for both the system in physiological (pH [~] 7) and high (pH [~] 10) environments. Electrostatic interactions dominated complexation, with PMF profiles revealing stronger binding affinity for Gal-PAMAM/siRNA at pH 7. siRNA displayed lower flexibility at pH 7 for both complexes, indicating enhanced stability. These findings suggest that Gal-PAMAM dendrimers at physiological pH hold promise for efficient siRNA delivery due to their superior complex stability and interaction strength. However, in polar solvents, Gal-PETIM exhibits hydrophobic behavior, enabling rapid delivery.

biophysics↗

bioRxiv2024

Self-assembly of mycolic acid in water: monolayer or bilayer

The enduring pathogenicity of Mycobacterium tuberculosis can be attributed to its lipid-rich cell wall, with mycolic acids (MAs) being a significant constituent. Different MAs fluidity and structural adaptability within the bacterial cell envelope significantly influence their physicochemical properties, operational capabilities, and pathogenic potential. Therefore, an accurate conformational representation of various MAs in aqueous media can provide insights into their potential role within the intricate structure of the bacterial cell wall. We have carried out the MD simulations of MAs in an aqueous solution and shed light on the various structural properties such as thickness, order parameters, area-per-MAs, conformational changes, and principle component (PC) in the single component and mixed MAs monolayer. The different conformational populations in the monolayer have been estimated using the distance-based analysis between the function groups represented as W, U, and Z-conformations that lead to the fold of the MAs chain in the monolayer. Additionally, we have also simulated the mixture of alpha-MA (-MA or AMA), methoxy-MA (MMA), and keto-MA (KMA) with 56% AMA, 40 % MMA, and 14 % KMA composition. The thickness of the MAs monolayer was observed to range from 5 nm to 7 nm with an average 820 kg/m3 density for -MA, MMA, and KMA quantitative agreement with experimental results. The mero-chain (long chain), consisting of a functional group at the proximal and distal positions, tends to fold and exhibit a more disordered phase than the short chain. The keto-MA showed the greatest WUZ total conformations (35.32 %) with decreasing trend of eZ > eU > aU > aZ folds in both single component and mixture. Our results are in quantitative agreement with the experimental observations. The most minor population of sZ folds (0.75 % in a single component and 1.1 % in a mixture). However, eU and aU folds are most probable for the AMA and MMA. One striking observation is the abundance of MA conformers beyond the known WUZ convention because of the wide range distribution of intramolecular distances and change in dihedral angles. From the thermodynamic viewpoint, all monolayers were found to be stable in nature. The results from enhanced simulation revealed that changes in the magnitude of minimum free energy of the MAs are in order of KMA > AMA > MMA, and keto-MA exhibits more resistance (based on free energy values) for the drug molecules to permeate through the monolayer.

biophysics↗

bioRxiv2023

Drug-bacterial membrane interactions: A Tale of two force fields

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), a gram-positive bacteria, is known to infect and kill millions of people worldwide, specifically in poor and developing countries. M.tb has unique characteristics in terms of the presence of an extraordinarily thick cell wall structure, mainly composed of mycolic acid (MA) and arabinogalactan (AG). Between these components, mycolic acid is of particular interest because it exhibits extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. Hence, it is extremely useful to study the interactions between drug molecules and mycolic acids in order to better design potential TB medicine. On that premise, the present work aims to computationally model mycolic acid monolayer and probe its permeability against some first-line TB drugs, namely ethambutol, ethionamide, and isoniazid. It is a known fact that such modelling strongly depends on the interaction parameters used. The current study addresses this issue by employing two widely used force fields-GROMOS 54A7-ATB (hereafter GROMOS) united atom force fields and CHARMM36 (hereafter CHARMM) all-atom force fields to collate the drug-mycolic acid interplay. Our findings indicate that both force fields provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ for the monolayer permeability. Mycolic acid monolayer generally exhibited a higher free energy barrier of crossing using CHARMM FF, while GROMOS parameters provide better stability of drug molecules on the monolayer surface, which can be attributed to the greater electrostatic potential at the monolayer-water interface. Both the force field parameters predicted the highest resistance against ethambutol, the most soluble molecule. However, significant differences can be recorded for the other two molecules with the change in the interaction parameter set. In summary, our study provides insight into the dependency of in silico modelling of membranes on force field parameters together with the guidelines to investigate the drug-membrane interactions consisting of non-standard lipids/fatty acids.

biophysics↗

bioRxiv2023

DNA Tetrahedral Nanocages as a Promising Nanocarrier for Dopamine Delivery in Neurological Disorders

Dopamine is a neurotransmitter in the central nervous system that is essential for many bodily and mental processes, and a lack of it can cause Parkinsons disease. DNA tetrahedral (TD) nanocages are promising in bio-nanotechnology, especially as a nanocarrier. TD is highly programmable, biocompatible, and capable of cell differentiation and proliferation. It also has tissue and blood-brain barrier permeability, making it a powerful tool that could overcome potential barriers in treating neurological disorders. In this study, we used DNA-TD as a carrier for Dopamine to cells and zebrafish embryos. We investigated the mechanism of complexation between TD and dopamine hydrochloride using gel electrophoresis, fluorescence and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and molecular dynamic (MD) simulation tools. Further, we demonstrate these Dopamine-loaded DNA tetrahedral nanostructures cellular uptake and differentiation ability in SH-SY5Y neuroblastoma cells. Furthermore, we extended the study to zebrafish embryos as a model organism to examine survival and uptake. The research provides valuable insights into the complexation mechanism and cellular uptake of dopamine-loaded DNA tetrahedral nanostructures, paving the way for further advancements in nanomedicine for Parkinsons disease and other neurological disorders.

bioengineering↗

bioRxiv2022

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis

Hyperphosphorylated guanosine nucleotide (p)ppGpp, synthesized by Rel proteins, regulates the stringent response pathway responsible for biofilm growth and persister cell formation in the stationary phase of mycobacteria. The discovery of vitamin C as a potent inhibitor of Rel protein activities raises the prospect of such a tetrone lactone to prevent biofilm growth and persister cell formation. The closely related isotetrone lactone derivatives are identified in the present study as potent inhibitors of the above processes in a mycobacterium. Isotetrone lactone derivatives are synthesized from appropriate -ketocarboxylic acids, derived from the a-amino acids. Aldol condensation with formaldehyde, followed by the lactone formation, completes synthesis of isotetrone derivatives, possessing varied substituents at C-4 carbon, in good yields. A series of biochemical evaluations of biofilm growth and persister cell formation in M. smegmatis is conducted. Among the derivatives, isotetrone possessing phenyl substituent at C-4 carbon completely inhibit the biofilm formation at 400 g mL-1 concentration, 84 h of post-exposure, followed by a moderate inhibition by the isotetrone possessing p-hydroxyphenyl substituent. Whereas, the latter isotetrone inhibits the growth of cells at 400 g mL-1 f.c. when monitored for 2 weeks, under PBS starvation condition. Isotetrones also potentiate the inhibition of antibiotic tolerant regrowth of cells by ciprofloxacin antibiotic (0.75 g mL-1) and thus act as bio-enhancers. The combination is shown to significantly arrest the emergence of ciprofloxacin-resistant genetic mutants. The observations suggest that isotetrones in combination with ciprofloxacin are therapeutically superior when administered together. Systematic molecular dynamics studies show that isotetrone derivative binds to Rel protein more efficiently than vitamin C and the binding is aided by hydrogen bonding, van der Waals and electrostatic interactions at a binding site possessing serine, threonine, lysine and arginine residues. The present study establishes that the identified isotetrone derivatives (i) act as inhibitors of M. smegmatis biofilm growth and (ii) arrest the re-emergence of recalcitrant persister cells when administered together with ciprofloxacin antibiotic. Results of this study establish that isotetrones as new chemical entities that interfere with stringent response pathways in a mycobacterium under stress and permit overcoming the multidrug-resistant persister cell emergence in the bacterium.

microbiology↗

bioRxiv2022

Molecular Dynamics Simulations Show How Antibodies May Rescue HIV-1 Mutants Incapable of Infecting Host Cells

High mutation and replication rates of HIV-1 result in the continuous generation of variants, allowing it to adapt to changing host environments. Mutations often have deleterious effects, but variants carrying them are rapidly purged. Surprisingly, a particular variant incapable of entering host cells was found to be rescued by host antibodies targeting HIV-1. Understanding the molecular mechanism of this rescue is important to develop and improve antibody-based therapies. To unravel the underlying mechanisms, we performed fully atomistic molecular dynamics simulations of the HIV-1 gp41 trimer responsible for viral entry into host cells, its entry-deficient variant, and its complex with the rescuing antibody. We find that the Q563R mutation, which the entry-deficient variant carries, prevents the native conformation of the gp41 6-helix bundle required for entry and stabilizes an alternative conformation instead. This is the consequence of substantial changes in the secondary structure and interactions between the domains of gp41. Binding of the antibody F240 to gp41 reverses these changes and re-establishes the native conformation, resulting in rescue. To test the generality of this mechanism, we performed simulations with the entry-deficient L565A variant and antibody 3D6. We find that 3D6 binding was able to reverse structural and interaction changes introduced by the mutation and restore the native gp41 conformation. Viral variants may not only escape antibodies but be aided by them in their survival, potentially compromising antibody-based therapies, including vaccination and passive immunization. Our simulation framework could serve as a tool to assess the likelihood of such resistance against specific antibodies.

biophysics↗

bioRxiv2021

Computational study on Strontium ion modified Fibronectin-Hydroxyapatite interaction

Protein adsorption is the first key step in cell-material interaction. The initial phase of such adsorption process can only be probed using modelling approaches like molecular dynamics (MD) simulation. Despite a large number of studies on the adsorption behaviour of proteins on different biomaterials including hydroxyapatite (HA); little attention has been paid towards quantitative assessment of the effects of various physicochemical influencers like surface modification, pH, and ionic strength. Among these factors, surface modification through isomorphic substitution of foreign ions inside the apatite structure is of particular interest in the context of protein-HA interaction as it is widely used to tailor the biological response of HA. Given this background, we present here the molecular-level understanding of fibronectin (FN) adsorption mechanism and kinetics on Sr2+-doped HA (001) surface, at 300K by means of all-atom molecular dynamics simulation. Electrostatic interaction involved in adsorption of FN on HA was found to be significantly modified in presence of Sr2+ doping in apatite lattice. In harmony with the published experimental observations, the Sr-doped surface was found to better support FN adhesion compared to pure HA, with 10 mol% Sr-doped HA exhibiting best FN adsorption. Sr2+ ions also influence the stability of the secondary structure of FN, as observed from the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. The presence of Sr2+ enhances the flexibility of specific residues (residue no. 20-44, 74-88) of the FN module. Rupture forces to disentangle FN from the biomaterials surface, obtained from steered molecular dynamics (SMD) simulations, were found to corroborate well with the results of equilibrium MD simulations. One particular observation is that, the availability of RGD motif for the interaction with cell surface receptor integrin is not significantly influenced by Sr2+ substitution. Summarizing, the present work establishes a quantitative foundation towards the molecular basis of the earlier experimentally validated better cytocompatibility of Sr-doped HA. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/461618v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@19614a6org.highwire.dtl.DTLVardef@25b39eorg.highwire.dtl.DTLVardef@13368eborg.highwire.dtl.DTLVardef@2d44ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

Mechanistic Insights into the Effects of Key Mutations on SARS-CoV-2 RBD-ACE2 Binding

Some recent SARS-CoV-2 variants appear to have increased transmissibility than the original strain. An underlying mechanism could be the improved ability of the variants to bind receptors on target cells and infect them. In this study, we provide atomic-level insight into the binding of the receptor binding domain (RBD) of the wild-type SARS-CoV-2 spike protein and its single (N501Y), double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants to the human ACE2 receptor. Using extensive all-atom molecular dynamics simulations and advanced free energy calculations, we estimate the associated binding affinities and binding hotspots. We observe significant secondary structural changes in the RBD of the mutants, which lead to different binding affinities. We find higher binding affinities of the double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants than the wild type and the N501Y variant, which could contribute to the higher transmissibility of recent variants containing these mutations.

biophysics↗