Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex

Wed, 06/29/2022 - 05:51 By Anonymous

Titolo: Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex
Abstract: The recent emergence of the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for the coronavirus disease 2019 (COVID-19), is causing a global pandemic that poses enormous challenges to global public health and economies. SARS-CoV-2 host cell entry is mediated by the interaction of the viral transmembrane spike glycoprotein (S-protein) with the angiotensin-converting enzyme 2 gene (ACE2), an essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Accordingly, this work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular receptor ACE2 that provides qualitative and quantitative insights into the main molecular determinants in virus/receptor recognition. In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498, T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain are determined as true hot spots, contributing to shaping and determining the stability of the relevant protein-protein interface. Overall, these results could be used to estimate the binding affinity of the viral protein to different allelic variants of ACE2 receptors discovered in COVID-19 patients and for the effective structure-based design and development of neutralizing antibodies, vaccines, and protein/protein inhibitors against this terrible new coronavirus.

Structure and binding thermodynamics of viologen-phosphorous dendrimers to human serum albumin: A combined computational/experimental investigation

Wed, 06/29/2022 - 05:51 By Anonymous

Titolo: Structure and binding thermodynamics of viologen-phosphorous dendrimers to human serum albumin: A combined computational/experimental investigation
Abstract: Low-generation viologen-phosphorous dendrimers (VPDs) can be exploited as novel therapeutic agents, since they efficiently inhibit aggregation of amyloid-β into fibrils and are active against several strains of microorganisms. Human serum albumin (HSA), the most abundant plasma protein, is playing an increasing role as drug carrier in the clinical setting. Therefore, with the aim of exploiting HSA as a potential carrier for VPDs, in this work we performed a preliminary investigation of the interaction of six different VPDs 1–6 with HSA using a combined computational/experimental approach. First, different modeling techniques were employed to i) determine the dendrimer binding site on the HSA surface; ii) derive the free energy change ΔGb involved in each dendrimer/HSA complex formation; iii) analyze in details all molecular determinants contributing to ΔGb, and iv) evaluate the eventual HSA structural variations induced by dendrimer binding. All modeling predictions were next validated using a series of experimental techniques, including isothermal titration calorimetry (ITC), circular dichroism (CD), and fluorescence quenching and decay. In aggregate, the results from this study allowed us to rank the affinity of the different viologen-phosphorous dendrimers 1–6 towards HSA and to formulate a molecular-based rationale for the differential binding thermodynamics of the resulting dendrimer/HSA complexes. According to our data, HSA can successfully and selectively bind VPDs 1–6, dendrimer 4 being the best cargo for this endogenous protein nanocarrier.