Biology subjects

Barroso da Silva, F. L.

Publications and source records attributed to Barroso da Silva, F. L..

11 recordsLinked to original sources

bioRxiv2026

ARID-sf: A physics-informed Deep Learning scoring function to improve Antibody-Antigen docking model ranking

Accurate prediction of antibody-antigen (Ab-Ag) complexation is crucial for understanding immune responses, diagnostics, and the development of therapeutic antibodies. While molecular docking generates conformations, current scoring functions struggle to identify nearnative poses, particularly for Ab-Ag interactions. We present ARID-sf (Antibody-antigen Residue Interface Docking scoring function), which combines classical force field potentials with structural features and protein language model embeddings through a self-attention-based neural network architecture. ARID-sf was trained on >1.5 million docking models and evaluated across four independent test sets comprising 806 cases and 700,000+ docking models. ARID-sf consistently outperforms other functions on increasingly challenging docking scenarios. Critically, ARID-sf maintains performance across diverse sequence identities and increasing conformational change required to reach the bound state, starting with unbound components, demonstrating robust generalization. ARID-sf is parallelizable and can process thousands of docking models per minute, enabling practical application in computational Ab engineering pipelines. The code, trained network, and complete pipeline are freely available at https://github.com/DSIMB/ARID-sf.git.

bioinformatics↗

bioRxiv2025

ANABAG: Annotated Antibody Antigen dataset with unique features for Antibody Engineering Applications

The analysis and prediction of antibody-antigen (Ab-Ag) interactions often overlook critical structural features such as glycosylation, physical chemical conditions like pH and salt concentration, as well as the lack of standardized criteria for selecting complexes based on structural properties and sequence identity. Common practices in dataset construction rely on removing redundancy using sequence identity thresholds, which can inadvertently exclude complexes with alternative binding modes that share identical sequences. To enable more precise Ab-Ag modeling and antibody engineering, it is essential to incorporate richer structural and physical information into both physics-based and machine learning models. To address these limitations, we present ANABAG, a new curated dataset of Ab-Ag complexes annotated at the residue level with UniProt sequence information and enriched with a wide range of structural and physicochemical features. The dataset allows flexible filtering of complexes using a variety of descriptors available at both the complex and residue levels. Selected features are ready to use in machine learning workflows, while the structural files are compatible with antibody design and docking pipelines like Rosetta or Haddock. The complete dataset is available on Zenodo, and all accompanying scripts and usage documentation can be accessed via GitHub at https://github.com/DSIMB/anabag-handler.git.

bioinformatics↗

bioRxiv2024

Studying self-assembly of norovirus capsid by a combination of in silico methods

Understanding how macromolecular assembly occurs is a fundamental and challenging problem because spontaneous, precise assembly is at the center of most biological processes. It is an elaborate process that requires non-covalent stable interactions between partners to stabilize the desired architecture for a specific purpose. One of the advantages of virus models is that under adequate conditions capsid proteins can be efficiently assembled in vitro in the absence of any other component, providing simplified experimental models that can be rigorously characterized. The present study aims at describing the initial steps of molecular self-assembly of norovirus-like particles (NoVLPs, composed solely of the major norovirus capsid protein VP1), by combining in silico computational approaches to explore complementary physical properties. We show that this strategy allows not only recapitulating but also revising a former NoVLP assembly model. Our approach can be applied and extended to other problems in macromolecular assembly.

bioinformatics↗

bioRxiv2022

Electrostatic features for the Receptor binding domain of SARS-COV-2 wildtype and its variants. Compass to the severity of the future variants with the charge rule.

Electrostatic intermolecular interactions are important in many aspects of biology. We have studied the main electrostatic features involved in the interaction of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with the human receptor Angiotensin-converting enzyme 2 (ACE2). As the principal computational tool, we have used the FORTE approach, capable to model proton fluctuations and computing free energies for a very large number of protein-protein systems under different physical-chemical conditions, here focusing on the RBD-ACE2 interactions. Both the wild-type and all critical variants are included in this study. From our large ensemble of extensive simulations, we obtain, as a function of pH, the binding affinities, charges of the proteins, their charge regulation capacities, and their dipole moments. In addition, we have calculated the pKas for all ionizable residues and mapped the electrostatic coupling between them. We are able to present a simple predictor for the RBD-ACE2 binding based on the data obtained for Alpha, Beta, Gamma, Delta, and Omicron variants, as a linear correlation between the total charge of the RBD and the corresponding binding affinity. This "RBD charge rule" should work as a quick test of the degree of severity of the coming SARS-CoV-2 variants in the future. Categories and Subject Descriptors:

biophysics↗

bioRxiv2022

NS1 from Two Zika Virus Strains Differently Interact with a Membrane: A Plausible Explanation for their Differential Virulence

Zika virus (ZIKV) from Uganda (UG) expresses a phenotype related to fetal loss whereas the variant from Brazil (BR) induces microcephaly in neonates. The differential virulence has a direct relation to biomolecular mechanisms that make one strain more aggressive than the other. The non-structural protein 1 (NS1) is a key viral toxin to comprehend these viral discrepancies because of its versatility in many processes of the virus life cycle. Here, we aim to examine through coarse-grained models and molecular dynamics simulations the protein-membrane interactions for both NS1ZIKV-UG and NS1ZIKV-BR dimers. A first evaluation allowed us to establish that the NS1 proteins, in the membrane presence, explore new conformational spaces when compared to systems simulated without a lipid bilayer. These events derive from both differential coupling patterns and discrepant binding affinities to the membrane. The N-terminal domain, intertwined loop, and greasy finger proposed previously as binding membrane regions were also computationally confirmed by us. The anchoring sites have aromatic and ionizable residues that manage the assembly of NS1 toward the membrane, especially for the Ugandan variant. Furthermore, the protein-membrane interaction induces perturbation in the distal part related to putative epitopes. These results open up new strategies for the treatment of flaviviruses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/487413v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@11023e9org.highwire.dtl.DTLVardef@a5d417org.highwire.dtl.DTLVardef@1073b91org.highwire.dtl.DTLVardef@1d7cffe_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

Self-association features of NS1 proteins from different flaviviruses

Flaviviruses comprise a large group of arboviral species that are distributed in several countries of the tropics, neotropics, and some temperate zones. Since they can produce neurological pathologies or vascular damage, there has been intense research seeking better diagnosis and treatments for their infections in the last decades. The flavivirus NS1 protein is a relevant clinical target because it is involved in viral replication, immune evasion, and virulence. Being a key factor in endothelial and tissue-specific modulation, NS1 has been largely studied to understand the molecular mechanisms exploited by the virus to reprogram host cells. A central part of the viral maturation processes is the NS1 oligomerization because many stages rely on these protein-protein assemblies. In the present study, the self-associations of NS1 proteins from Zika, Dengue, and West Nile viruses are examined through constant-pH coarse-grained biophysical simulations. Free energies of interactions were estimated for different oligomeric states and pH conditions. Our results show that these proteins can form both dimers and tetramers under conditions near physiological pH even without the presence of lipids. Moreover, pH plays an important role mainly controlling the regimes where van der Waals interactions govern their association. Finally, despite the similarity at the sequence level, we found that each flavivirus has a well-characteristic protein-protein interaction profile. These specific features can provide new hints for the development of binders both for better diagnostic tools and the formulation of new therapeutic drugs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/484429v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1221d69org.highwire.dtl.DTLVardef@b90429org.highwire.dtl.DTLVardef@c039c3org.highwire.dtl.DTLVardef@1039cc_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies

SARS-CoV-2 has caused immeasurable damage worldwide and available treatments with high efficacy are still scarce. With the continuous emergence of new variants of the virus, such as Omicron, Alpha, Beta, Gamma, and Delta - the so-called variants of concern, the available therapeutic and prevention strategies had to return to the experimental trial to verify their effectiveness against them. This work aims to expand the knowledge about the SARS-CoV-2 receptor-binding domain (RBD) interactions with cell receptors and monoclonal antibodies (mAbs). Special attention is given to the Omicron variant and its comparison with the others, including its sublineage BA.2 and two new ones (B.1.640.1 and B.1.640.2/IHU) recently found in France. By using constant-pH Monte Carlo simulations, the free energy of interactions between the SARS-CoV-2 receptor-binding domain (RBD) from different variants and several partners (Angiotensin-Converting Enzyme-2 (ACE2) polymorphisms and several mAbs) were calculated. It was evaluated both the impact of mutations for the RBD-ACE2 and how strongly each of mAb can bind to the virus RBD, which can indicate their therapeutic potential for neutralization. RBD-ACE2-binding affinities were higher for two ACE2 polymorphisms typically found in Europeans (rs142984500 and rs4646116), indicating that these types of polymorphisms may be related to genetic susceptibility to COVID-19. The antibody landscape was computationally investigated with the largest set of mAbs so far in the literature. From the 33 studied binders, groups of mAbs were identified with weak (e.g. S110 and Ab3b4), medium (e.g. CR3022), and strong binding affinities (e.g. P01, S2K146 and S230). All the mAbs with strong binding capacity could also bind to the RBD from SARS-CoV-1, SARS-CoV-2 wt, and all studied variants. These mAbs and especially their combination are amenable to experimentation and clinical trials because of their high binding affinities and neutralization potential for current known virus mutations and a universal coronavirus.

biophysics↗

bioRxiv2022

Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants

A highly efficient and robust multiple scales in silico protocol, consisting of atomistic constant charge Molecular Dynamics (MD), constant-charge coarse-grain (CG) MD and constant-pH CG Monte Carlo (MC), has been used to study the binding affinities, the free energy of complexation of selected antigen-binding fragments of the monoclonal antibody (mAbs) CR3022 (originally derived from SARS-CoV-1 patients almost two decades ago) and 11 SARS-CoV-2 variants including the wild type. CR3022 binds strongly to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein, but chooses a different site rather than the receptor-binding motif (RBM) of RBD, allowing its combined use with other mAbs against new emerging virus variants. Totally 235,000 mAbs structures were generated using the RosettaAntibodyDesign software, resulting in top 10 scored CR3022-RBD complexes with critical mutations and compared to the native one, all having the potential to block virus-host cell interaction. Of these 10 finalists, two candidates were further identified in the CG simulations to be clearly best against all virus variants, and surprisingly, all 10 candidates and the native CR3022 did exhibit a higher affinity for the Omicron variant with its highest number of mutations (15) of them all considered in this study. The multiscale protocol gives us a powerful rational tool to design efficient mAbs. The electrostatic interactions play a crucial role and appear to be controlling the affinity and complex building. Clearly, mAbs carrying a lower net charge show a higher affinity. Structural determinants could be identified in atomistic simulations and their roles are discussed in detail to further hint at a strategy towards designing the best RBD binder. Although the SARS-CoV-2 was specifically targeted in this work, our approach is generally suitable for many diseases and viral and bacterial pathogens, leukemia, cancer, multiple sclerosis, rheumatoid, arthritis, lupus, and more.

biophysics↗

bioRxiv2021

The Up state of the SARS-COV-2 Spike homotrimer favors an increased virulence for new variants

The COVID-19 pandemic has spread widely worldwide. However, as soon as the vaccines were released - the only scientifically verified and efficient therapeutic option thus far - a few mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged raising doubts about their efficiency. Therefore, this work aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor binding domain (RBD) and Angiotensin Converting Enzyme 2 (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state (the one in which the virus can interact with the cellular receptor ACE2) than due to alterations in the complexation RBD-ACE2, once the increased observed in the free energy values is small. Conversely, the South African variant (B.1.351), when compared with the wild type SARS-CoV-2, is much more stable in the opened state (either with one or two RBDs in the up position) than in the closed state (with the three RBDs in the down position). Such results contribute to the understanding of the natural history of disease and also to indicate possible strategies to both develop new therapeutic molecules and to adjust the vaccine doses for a higher production of B cells antibodies. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

bioinformatics↗

bioRxiv2020

On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2

A new betacoronavirus named SARS-CoV-2 has emerged as a new threat to global health and economy. A promising target for both diagnosis and therapeutics treatments of the new disease named COVID-19 is the coronavirus (CoV) spike (S) glycoprotein. By constant-pH Monte Carlo simulations and the PROCEEDpKa method, we have mapped the electrostatic epitopes for four monoclonal antibodies and the angiotensin-converting enzyme 2 (ACE2) on both SARS-CoV-1 and the new SARS-CoV-2 S receptor binding domain (RBD) proteins. We also calculated free energy of interactions and shown that the S RBD proteins from both SARS viruses binds to ACE2 with similar affinities. However, the affinity between the S RBD protein from the new SARS-CoV-2 and ACE2 is higher than for any studied antibody previously found complexed with SARS-CoV-1. Based on physical chemical analysis and free energies estimates, we can shed some light on the involved molecular recognition processes, their clinical aspects, the implications for drug developments, and suggest structural modifications on the CR3022 antibody that would improve its binding affinities for SARS-CoV-2 and contribute to address the ongoing international health crisis.

biophysics↗

bioRxiv2019

Repositioning septins within the core particle

Septins are GTP binding proteins considered to be a novel component of the cytoskeleton. They polymerize into filaments based on hetero-oligomeric core particles which, in humans, are either hexamers or octamers composed of two copies each of either three or four different septins from the 13 available. Not all combinations are possible as it is believed that these must obey substitution rules which determine that different septins must be derived from four distinct and well-established sub-groups. Here, we have purified and characterized one such combinations, SEPT5-SEPT6-SEPT7, and used TEM to derive the first structural information concerning its assembly. The full complex was purified using an affinity tag attached to only one of its components (SEPT7) and was able to bind to and perturb lipid bilayers. Although the complex assembled into elongated hexameric particles, the position of SEPT5 was incompatible with that predicted by the reported structure of SEPT2-SEPT6-SEPT7 based on the substitution rules. MBP-fusion constructs for SEPT5 and SEPT2 and immuno-staining clearly show that these septins occupy the terminal positions of the SEPT5-SEPT6-SEPT7 and SEPT2-SEPT6-SEPT7 hexamers, respectively. In so doing they expose a so-called NC interface which we show to be more susceptible to perturbation at high salt concentrations. Our results show that the true structure of the hexamer is inverted with respect to that described previously and, as such, is more compatible with that reported for yeast. Taken together, our results suggest that the mechanisms involved in spontaneous self-assembly of septin core particles and their filaments deserve further reflection.

biochemistry↗