Prediction and Evaluation of Protein Aggregation with Computational Methods.

Protein and peptide aggregation has recently become one of the most studied biomedical problems due to its central role in several neurodegenerative disorders and of biotechnological importance. Multiple in silico methods, databases, tools, and algorithms have been developed to predict aggregation of proteins and peptides to better understand fundamental mechanisms of various aggregation diseases. Here, we attempt to provide a brief overview of bioinformatic methods and tools to better understand molecular mechanisms of aggregation disorders.

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.

Stability and cavitation of nanobubble: Insights from large-scale atomistic molecular dynamics simulations.

We perform large-scale atomistic simulations of a system containing 12 × 106 atoms, comprising an oxygen gas-filled bubble immersed in water, to understand the stability and cavitation induced by ultrasound. First, we propose a method to construct a bubble/water system. For a given bubble radius, the pressure inside the bubble is estimated using the Young-Laplace equation.

Neuropilin-1 Protein May Serve as a Receptor for SARS-CoV-2 Infection: Evidence from Molecular Dynamics Simulations.

The binding of the virus to host cells is the first step in viral infection. Human cell angiotensin converting enzyme 2 (ACE2) is the most popular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while other receptors have recently been observed in experiments. Neuropilin-1 protein (NRP1) is one of them, but the mechanism of its binding to the wild type (WT) and different variants of the virus remain unclear at the atomic level.

A Practical Guide to All-Atom and Coarse-Grained Molecular Dynamics Simulations Using Amber and Gromacs: A Case Study of Disulfide-Bond Impact on the Intrinsically Disordered Amyloid Beta.

Intrinsically disordered proteins (IDPs) pose challenges to conventional experimental techniques due to their large-scale conformational fluctuations and transient structural elements. This work presents computational methods for studying IDPs at various resolutions using the Amber and Gromacs packages with both all-atom (Amber ff19SB with the OPC water model) and coarse-grained (Martini 3 and SIRAH) approaches. The effectiveness of these methodologies is demonstrated by examining the monomeric form of amyloid-β (Aβ42), an IDP, with and without disulfide bonds at different resolutions.

Serotonin Promotes Vesicular Association and Fusion by Modifying Lipid Bilayers.

The primary event in chemical neurotransmission involves the fusion of a membrane-limited vesicle at the plasma membrane and the subsequent release of its chemical neurotransmitter cargo. The cargo itself is not known to have any effect on the fusion event. However, amphiphilic monoamine neurotransmitters (e.

Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.

Protein misfolding, aggregation, and fibril formation play a central role in the development of severe neurological disorders, including Alzheimer's and Parkinson's diseases. The structural stability of mature fibrils in these diseases is of great importance, as organisms struggle to effectively eliminate amyloid plaques. To address this issue, it is crucial to investigate the early stages of fibril formation when monomers aggregate into small, toxic, and soluble oligomers.

SARS-CoV-2 Omicron Subvariants Do Not Differ Much in Binding Affinity to Human ACE2: A Molecular Dynamics Study.

The emergence of the variant of concern Omicron (B.1.1.

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.

Amyloid- Tetramers and Divalent Cations at the Membrane/Water Interface: Simple Models Support a Functional Role.

Charge polarization at the membrane interface is a fundamental process in biology. Despite the lower concentration compared to the abundant monovalent ions, the relative abundance of divalent cations (Ca, Mg, Zn, Fe, Cu) in particular spaces, such as the neuron synapse, raised many questions on the possible effects of free multivalent ions and of the required protection of membranes by the eventual defects caused by the free forms of the cations. In this work, we first applied a recent realistic model of divalent cations to a well-investigated model of a polar lipid bilayer, di-myristoyl phosphatidyl choline (DMPC).

How soluble misfolded proteins bypass chaperones at the molecular level.

Subpopulations of soluble, misfolded proteins can bypass chaperones within cells. The extent of this phenomenon and how it happens at the molecular level are unknown. Through a meta-analysis of the experimental literature we find that in all quantitative protein refolding studies there is always a subpopulation of soluble but misfolded protein that does not fold in the presence of one or more chaperones, and can take days or longer to do so.

Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study.

The folding of proteins into their native conformation is a complex process that has been extensively studied over the past half-century. The ribosome, the molecular machine responsible for protein synthesis, is known to interact with nascent proteins, adding further complexity to the protein folding landscape. Consequently, it is unclear whether the folding pathways of proteins are conserved on and off the ribosome.

Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations.

Nature confines hundreds of millimolar of amphiphilic neurotransmitters, such as serotonin, in synaptic vesicles. This appears to be a puzzle, as the mechanical properties of lipid bilayer membranes of individual major polar lipid constituents of synaptic vesicles [phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS)] are significantly affected by serotonin, sometimes even at few millimolar concentrations. These properties are measured by atomic force microscopy, and their results are corroborated by molecular dynamics simulations.

Molecular dynamics simulation of cancer cell membrane perforated by shockwave induced bubble collapse.

It has been widely accepted that cancer cells are softer than their normal counterparts. This motivates us to propose, as a proof-of-concept, a method for the efficient delivery of therapeutic agents into cancer cells, while normal cells are less affected. The basic idea of this method is to use a water jet generated by the collapse of the bubble under shockwaves to perforate pores in the cell membrane.

Identifying inhibitors of NSP16-NSP10 of SARS-CoV-2 from large databases.

The COVID-19 pandemic, which has already claimed millions of lives, continues to pose a serious threat to human health, requiring the development of new effective drugs. Non-structural proteins of SARS-CoV-2 play an important role in viral replication and infection. Among them, NSP16 (non-structured protein 16) and its cofactor NSP10 (non-structured protein 10) perform C2'-O methylation at the 5' end of the viral RNA, which promotes efficient virus replication.

Protein aggregation rate depends on mechanical stability of fibrillar structure.

The formation of the fibrillar structure of amyloid proteins/peptides is believed to be associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Since the rate of aggregation can influence neurotoxicity, finding the key factors that control this rate is of paramount importance. It was recently found that the rate of protein aggregation is related to the mechanical stability of the fibrillar structure such that the higher the mechanical stability, the faster the fibril is formed.

SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation.

The emergence of the variant of concern Omicron (B.1.1.

Antibody-nanobody combination increases their neutralizing activity against SARS-CoV-2 and nanobody H11-H4 is effective against Alpha, Kappa and Delta variants.

The global spread of COVID-19 is devastating health systems and economies worldwide. While the use of vaccines has yielded encouraging results, the emergence of new variants of SARS-CoV-2 shows that combating COVID-19 remains a big challenge. One of the most promising treatments is the use of not only antibodies, but also nanobodies.

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity.

The amyloid cascade hypothesis states that senile plaques, composed of amyloid β (Aβ) fibrils, play a key role in Alzheimer's disease (AD). However, recent experiments have shown that Aβ oligomers are more toxic to neurons than highly ordered fibrils. The molecular mechanism underlying this observation remains largely unknown.

Determination of Multidirectional Pathways for Ligand Release from the Receptor: A New Approach Based on Differential Evolution.

Steered molecular dynamics (SMD) simulation is a powerful method in computer-aided drug design as it can be used to access the relative binding affinity with high precision but with low computational cost. The success of SMD depends on the choice of the direction along which the ligand is pulled from the receptor-binding site. In most simulations, the unidirectional pathway was used, but in some cases, this choice resulted in the ligand colliding with the complex surface of the exit tunnel.

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.