Pulling Forces Differentially Affect Refolding Pathways Due to Entangled Misfolded States in SARS-CoV-1 and SARS-CoV-2 Receptor Binding Domain.

Single-molecule force spectroscopy (SMFS) experiments can monitor protein refolding by applying a small force of a few piconewtons (pN) and slowing down the folding process. Bell theory predicts that in the narrow force regime where refolding can occur, the folding time should increase exponentially with increased external force. In this work, using coarse-grained molecular dynamics simulations, we compared the refolding pathways of SARS-CoV-1 RBD and SARS-CoV-2 RBD (RBD refers to the receptor binding domain) starting from unfolded conformations with and without a force applied to the protein termini.

Synonymous Mutations Can Alter Protein Dimerization Through Localized Interface Misfolding Involving Self-entanglements.

Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding substantially without changing the protein's amino acid sequence. Here, we use coarse-grain simulations of protein synthesis, post-translational dynamics, and dimerization to understand how synonymous mutations can influence the dimerization of two E. coli homodimers, oligoribonuclease and ribonuclease T.

Deciphering the free energy landscapes of SARS-CoV-2 wild type and Omicron variant interacting with human ACE2.

The binding of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein to the host cell receptor angiotensin-converting enzyme 2 (ACE2) is the first step in human viral infection. Therefore, understanding the mechanism of interaction between RBD and ACE2 at the molecular level is critical for the prevention of COVID-19, as more variants of concern, such as Omicron, appear. Recently, atomic force microscopy has been applied to characterize the free energy landscape of the RBD-ACE2 complex, including estimation of the distance between the transition state and the bound state, xu.

Cocktail of REGN Antibodies Binds More Strongly to SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces Its Neutralizing Ability.

A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19.

Electrostatic Interactions Explain the Higher Binding Affinity of the CR3022 Antibody for SARS-CoV-2 than the 4A8 Antibody.

A structural understanding of the mechanism by which antibodies bind SARS-CoV-2 at the atomic level is highly desirable as it can tell the development of more effective antibodies to treat Covid-19. Here, we use steered molecular dynamics (SMD) and coarse-grained simulations to estimate the binding affinity of the monoclonal antibodies CR3022 and 4A8 to the SARS-CoV-2 receptor-binding domain (RBD) and SARS-CoV-2 N-terminal domain (NTD). Consistent with experiments, our SMD and coarse-grained simulations both indicate that CR3022 has a higher affinity for SARS-CoV-2 RBD than 4A8 for the NTD, and the coarse-grained simulations indicate the former binds three times stronger to its respective epitope.

Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV?

The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, was declared a pandemic by the World Health Organization in March 2020. Genetically, SARS-CoV-2 is closely related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries from 2002 to 2003. Given the significant morbidity and mortality rate, the current pandemic poses a danger to all of humanity, prompting us to understand the activity of SARS-CoV-2 at the atomic level.

Heat-induced degradation of fibrils: Exponential vs logistic kinetics.

The degradation of fibrils under the influence of thermal fluctuations was studied experimentally by various groups around the world. In the first set of experiments, it was shown that the decay of fibril content, which can be measured by the ThT fluorescence assay, obeys a bi-exponential function. In the second series of experiments, it was demonstrated that when the monomers separated from the aggregate are not recyclable, the time dependence of the number of monomers belonging to the dominant cluster is described by a single-exponential function if the fraction of bound chains becomes less than a certain threshold.

A topological order parameter for describing folding free energy landscapes of proteins.

We studied the refolding free energy landscape of 26 proteins using the Go-like model. The distance between the denaturated state and the transition state, , was calculated using the Bell theory and the nonlinear Dudko-Hummer-Szabo theory, and its relation to the geometrical properties of the native state was considered in detail. We showed that none of the structural parameters, such as the contact order, protein length, and radius of cross section, correlate with for all classes of proteins.

Erythromycin leads to differential protein expression through differences in electrostatic and dispersion interactions with nascent proteins.

The antibiotic activity of erythromycin, which reversibly binds to a site within the bacterial ribosome exit tunnel, against many gram positive microorganisms indicates that it effectively inhibits the production of proteins. Similar to other macrolides, the activity of erythromycin is far from universal, as some peptides can bypass the macrolide-obstructed exit tunnel and become partially or fully synthesized. It is unclear why, at the molecular level, some proteins can be synthesized while others cannot.

Switch from thermal to force-driven pathways of protein refolding.

The impact of the quenched force on protein folding pathways and free energy landscape was studied in detail. Using the coarse-grain Go model, we have obtained the low, middle, and high force regimes for protein refolding under the quenched force. The folding pathways in the low force regime coincide with the thermal ones.

Aβ41 Aggregates More Like Aβ40 than Like Aβ42: In Silico and in Vitro Study.

Formation of intracellular plaques and small oligomeric species of amyloid β (Aβ) peptides inside neurons is a hallmark of Alzheimer's disease. The most abundant Aβ species in the brain are Aβ1-40 and Aβ1-42, which are composed, respectively, of 40 and 42 residues. Aβ1-42 differs from Aβ1-40 only in two residues, Ile41 and Ala42, yet it shows remarkably faster aggregation and greater neurotoxicity than Aβ1-40.