@article{neamtu_mocci_laaksonen_silva_2023, title={Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants}, volume={221}, ISSN={["1873-4367"]}, DOI={10.1016/j.colsurfb.2022.112986}, abstractNote={A highly efficient and robust multiple scales in silico protocol, consisting of atomistic Molecular Dynamics (MD), coarse-grain (CG) MD, and constant-pH CG Monte Carlo (MC), has been developed and used to study the binding affinities of selected antigen-binding fragments of the monoclonal antibody (mAbs) CR3022 and several of its here optimized versions against 11 SARS-CoV-2 variants including the wild type. Totally 235,000 mAbs structures were initially generated using the RosettaAntibodyDesign software, resulting in top 10 scored CR3022-like-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 the best against all SARS-CoV-2 variants. Surprisingly, all 10 candidates and the native CR3022 exhibited a higher affinity for the Omicron variant despite its highest number of mutations. 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. Studied mAbs carrying a more negative total 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 for 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.}, journal={COLLOIDS AND SURFACES B-BIOINTERFACES}, author={Neamtu, Andrei and Mocci, Francesca and Laaksonen, Aatto and Silva, Fernando L. Barroso}, year={2023}, month={Jan} }
 @article{giron_laaksonen_silva_2022, title={Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies}, ISSN={["1538-0254"]}, DOI={10.1080/07391102.2022.2095305}, abstractNote={SARS-CoV-2 remains a health threat with the continuous emergence of new variants. This work aims to expand the knowledge about the SARS-CoV-2 receptor-binding domain (RBD) interactions with cell receptors and monoclonal antibodies (mAbs). By using constant-pH Monte Carlo simulations, the free energy of interactions between the RBD from different variants and several partners (Angiotensin-Converting Enzyme-2 (ACE2) polymorphisms and various mAbs) were predicted. Computed RBD-ACE2-binding affinities were higher for two ACE2 polymorphisms (rs142984500 and rs4646116) typically found in Europeans which indicates a genetic susceptibility. This is amplified for Omicron (BA.1) and its sublineages BA.2 and BA.3. The antibody landscape was computationally investigated with the largest set of mAbs so far in the literature. From the 32 studied binders, groups of mAbs were identified from weak to strong binding affinities (e.g. S2K146). These mAbs with strong binding capacity and especially their combination are amenable to experimentation and clinical trials because of their high predicted binding affinities and possible neutralization potential for current known virus mutations and a universal coronavirus.Communicated by Ramaswamy H. Sarma}, journal={JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS}, author={Giron, Carolina Correa and Laaksonen, Aatto and Silva, Fernando Luis}, year={2022}, month={Jun} }
 @article{poveda-cuevas_etchebest_silva_2022, title={Self-association features of NS1 proteins from different flaviviruses}, volume={318}, ISSN={["1872-7492"]}, DOI={10.1016/j.virusres.2022.198838}, abstractNote={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.}, journal={VIRUS RESEARCH}, author={Poveda-Cuevas, Sergio A. and Etchebest, Catherine and Silva, Fernando L. Barroso da}, year={2022}, month={Sep} }
 @article{poveda-cuevas_silva_etchebest_2021, title={How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence}, volume={61}, ISSN={["1549-960X"]}, DOI={10.1021/acs.jcim.0c01377}, abstractNote={Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.}, number={3}, journal={JOURNAL OF CHEMICAL INFORMATION AND MODELING}, author={Poveda-Cuevas, Sergio A. and Silva, Fernando Luis and Etchebest, Catherine}, year={2021}, month={Mar}, pages={1516–1530} }
 @article{smith_fabiani_wang_ramesh_khan_santiso_silva_gorman_menegatti_2020, title={Exploring the physicochemical and morphological properties of peptide‐hybridized dendrimers (
            DendriPeps
            ) and their aggregates}, volume={58}, ISSN={2642-4150 2642-4169}, url={http://dx.doi.org/10.1002/pol.20200277}, DOI={10.1002/pol.20200277}, abstractNote={Abstract This article presents an integrated experimental and computational study of DendriPeps, a novel class of dendrimers featuring a polyamidoamine (PAMAM) backbone hybridized with peptide segments. Hydroxyl‐terminated Generation 2 (G.2) DendriPeps, comprising either four lysines (Lys) or four glutamic acids (Glu), and G.3 DendriPeps, comprising 8 Lys or 8 Glu, were first characterized in terms of hydrodynamic radius ( R h ) and ζ‐potential in aqueous solution. Unlike PAMAM dendrimers, DendriPeps form aggregates with R h between 60 and 980 nm and ζ‐potential between −130 and 80 mV despite their strong net charge. Upon application of shear, all aggregates disassemble into monomeric DendriPeps ( R h ~ 1–3 nm), but reform rapidly as shear is removed. Rheological characterization confirmed that DendriPep aggregates are disrupted by mild shear, but reform reversibly. Molecular dynamics simulations, informed by titrimetry, suggest that DendriPep aggregation derives from their multipolar structure and ability to rearrange the intermolecular/intramolecular pairing of titratable moieties at different pH values.}, number={16}, journal={Journal of Polymer Science}, publisher={Wiley}, author={Smith, Ryan J. and Fabiani, Thomas and Wang, Siyao and Ramesh, Srivatsan and Khan, Saad and Santiso, Erik and Silva, Fernando Luis Barroso and Gorman, Christopher and Menegatti, Stefano}, year={2020}, month={Jul}, pages={2234–2247} }
 @article{poveda-cuevas_etchebest_silva_2020, title={Identification of Electrostatic Epitopes in Flavivirus by Computer Simulations: The PROCEEDpKa Method}, volume={60}, ISSN={["1549-960X"]}, DOI={10.1021/acs.jcim.9b00895}, abstractNote={Viruses are enthusiastically studied due to the great impact that these organisms can have on human health. Computational approaches can contribute offering tools that can shed light on important molecular mechanisms that help to design new diagnostic procedures. Several cellular processes between the immune-host system and the pathogenic organism are dependent on specific intermolecular interactions. In this study, we evaluated theoretical approaches to understand some properties of the antigen–antibody interactions considering the titratable properties of all ionizable residues of the nonstructural viral protein 1 (NS1) of the West Nile virus (WNV) and the Zika virus (ZIKV). Constant-pH Monte Carlo simulations were performed to estimate electrostatic properties such as the pKa shifts (ΔpKa). We proposed an alternative criterion for the discrimination of antigenic residues based on ΔpKas. Our outcomes were analyzed by an evaluation of the sensitivity and specificity through a receiver operating characteristic (ROC). As a starting point, we used the known crystallographic structure for the complex of NS1WNV(176–352) and the specific antibody 22NS1 (PDB ID 4OII) to differentiate the residues belonging to that interface. With an optimal threshold for the absolute value of the pKa shifts, we found that is possible to predict antigenic epitopes reproducing the interfaces as defined by the X-ray structure. After this validation, we evaluated theoretical predictions based on protein–protein (PP) complexation simulations. From them, we observe amino acids with an antigenic potential and defined the optimum threshold that was applied for two strains of ZIKV (i.e., Uganda and Brazil). Several ionizable residues with antigenic capacity were identified. This is favorably related to some studies that show the high immunogenicity of secreted NS1. This approach opens up an important discussion about what are termed here “electrostatic epitopes” and how they work as an important reference in the paratope–epitope interaction for viral systems.}, number={2}, journal={JOURNAL OF CHEMICAL INFORMATION AND MODELING}, author={Poveda-Cuevas, Sergio A. and Etchebest, Catherine and Silva, Fernando L.}, year={2020}, month={Feb}, pages={944–963} }
 @article{giron_laaksonen_silva_2020, title={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}, volume={285}, ISSN={["1872-7492"]}, DOI={10.1016/j.virusres.2020.198021}, abstractNote={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.}, journal={VIRUS RESEARCH}, author={Giron, Carolina Correa and Laaksonen, Aatto and Silva, Fernando L.}, year={2020}, month={Aug} }
 @article{pasquali_frezza_silva_2019, title={Coarse-grained dynamic RNA titration simulations}, volume={9}, ISSN={["2042-8901"]}, DOI={10.1098/rsfs.2018.0066}, abstractNote={Electrostatic interactions play a pivotal role in many biomolecular processes. The molecular organization and function in biological systems are largely determined by these interactions. Owing to the highly negative charge of RNA, the effect is expected to be more pronounced in this system. Moreover, RNA base pairing is dependent on the charge of the base, giving rise to alternative secondary and tertiary structures. The equilibrium between uncharged and charged bases is regulated by the solution pH, which is therefore a key environmental condition influencing the molecule’s structure and behaviour. By means of constant-pH Monte Carlo simulations based on a fast proton titration scheme, coupled with the coarse-grained model HiRE-RNA, molecular dynamic simulations of RNA molecules at constant pH enable us to explore the RNA conformational plasticity at different pH values as well as to compute electrostatic properties as local p K a values for each nucleotide.}, number={3}, journal={INTERFACE FOCUS}, author={Pasquali, S. and Frezza, E. and Silva, F. L.}, year={2019}, month={Jun} }