Mutations in RBD of SARS-CoV-2 Omicron variant result stronger binding to human ACE2 protein

The spreading of SARS-CoV-2 virus resulted the COVID-19 pandemic, which has caused more than 5 millions of death globally. Several major variants of SARS-CoV-2 have emerged and placed challenges in controlling the infections. The recently emerged Omicron variant raised serious concerns about reducing efficacy of antibodies or vaccines, due to its vast mutations. We modelled the complex structure of human ACE2 protein and the receptor binding domain of Omicron variant, then conducted atomistic molecular dynamics simulations to study the binding interactions. The analysis shows that the Omicron variant RBD binds more strongly to the human ACE2 protein than the original strain. The mutation at the ACE2-RBD interface enhanced the tight binding by increasing hydrogen bonding interaction and enlarging buried solvent accessible surface area.

A Binary Matrix Method to Enumerate, Hierarchically Order and Structurally Classify Peptide Aggregation

Protein aggregation is a common and complex phenomenon in biological processes, yet a robust analysis of this aggregation process remains elusive. The commonly used methods such as centre-of-mass to centre-of-mass (COM-COM) distance, the radius of gyration (Rg), hydrogen bonding (HB) and solvent accessible surface area (SASA) do not quantify the aggregation accurately. Herein, a new and robust method that uses an aggregation matrix (AM) approach to investigate peptide aggregation in a MD simulation trajectory is presented. A nxn two-dimensional aggregation matrix (AM) is created by using the inter-peptide CA-CA cut-off distances which are binarily encoded (0 or 1). These aggregation matrices are analysed to enumerate, hierarchically order and structurally classify the aggregates. Moreover, the comparison between the present AM method and the conventional Rg, COM-COM and HB methods shows that the conventional methods grossly underestimate the aggregation propensity. Additionally, the conventional methods do not address the hierarchy and structural ordering of the aggregates, which the present AM method does. Finally, the present AM method utilises only nxn two-dimensional matrices to analyse aggregates consisting of several peptide units. To the best of our knowledge, this is a maiden approach to enumerate, hierarchically order and structurally classify peptide aggregation.

Identifying signatures of proteolytic stability and monomeric propensity in O-glycosylated insulin using molecular simulation

Insulin has been commonly adopted as a peptide drug to treat diabetes given its ability to facilitate the uptake of glucose from the blood. The development of oral insulin remains elusive over decades owing to its susceptibility to the enzymes in the gastrointestinal tract and poor permeability through the intestinal epithelium upon dimerization. Recent experimental studies have revealed that certain O-linked glycosylation patterns could enhance insulin’s proteolytic stability and reduce its dimerization propensity, but the understanding of such phenomena at the molecular level is still evasive. To address this challenge, we propose and test several structural determinants that could potentially in uence insulin’s proteolytic stability and dimerization propensity. We used these as the metrics to assess the properties of interest from 10 s aggregate molecular dynamics of each of 12 targeted insulin glyco-variants from multiple wild-type crystal structures. We found that glycan-involved hydrogen bonds and glycan-dimer occlusion were useful metrics predicting the proteolytic stability and dimerization propensity of insulin, as was in part the solvent accessible surface area of proteolytic sites, while other plausible metrics were not generally predictive. This work helps better explain how O-linked glycosylation in uences the proteolytic stability and monomeric propensity of insulin, illuminating a path towards rational molecular design of insulin glycoforms.

Identifying signatures of proteolytic stability and monomeric propensity in O-glycosylated insulin using molecular simulation

Insulin has been commonly adopted as a peptide drug to treat diabetes given its ability to facilitate the uptake of glucose from the blood. The development of oral insulin remains elusive over decades owing to its susceptibility to the enzymes in the gastrointestinal tract and poor permeability through the intestinal epithelium upon dimerization. Recent experimental studies have revealed that certain O-linked glycosylation patterns could enhance insulin’s proteolytic stability and reduce its dimerization propensity, but the understanding of such phenomena at the molecular level is still evasive. To address this challenge, we propose and test several structural determinants that could potentially in uence insulin’s proteolytic stability and dimerization propensity. We used these as the metrics to assess the properties of interest from 10 s aggregate molecular dynamics of each of 12 targeted insulin glyco-variants from multiple wild-type crystal structures. We found that glycan-involved hydrogen bonds and glycan-dimer occlusion were useful metrics predicting the proteolytic stability and dimerization propensity of insulin, as was in part the solvent accessible surface area of proteolytic sites, while other plausible metrics were not generally predictive. This work helps better explain how O-linked glycosylation in uences the proteolytic stability and monomeric propensity of insulin, illuminating a path towards rational molecular design of insulin glycoforms.

Thermodynamically effective molecular surfaces for more efficient study of condensed-phase thermodynamics

Evaluation of molecular surfaces plays the key role in a wide range of cutting-edge scientific fields and technologies, due to the well-characterized dependency between molecular surfaces and condensed phase thermodynamics. Numerous methods to evaluate molecular surfaces such as van-der-Waals and solvent accessible surface areas and various parameterizations for each one, have been proposed in the literature and typically yield quite diverse estimations of molecular surfaces. Despite this diversity, numerous successful applications have been reported for each one, which has become possible via ad-hoc modifications and parametrizations employed to accommodate inappropriately defined molecular surfaces. The main aim of the present study is to propose “thermodynamically effective” molecular surface which unlike the conventionally accepted molecular surfaces, can be defined only uniquely, can be measured experimentally for each molecule directly and straightforwardly, is defined based on a well-characterized theoretically described dependency between molecular surfaces and solution thermodynamics, and is highly accurate in evaluating various thermodynamics quantities in solution for a wide temperature range and different types of molecules, without requiring any ad-hoc modification.

Protein–Protein Connections—Oligomer, Amyloid and Protein Complex—By Wide Line 1H NMR

The amount of bonds between constituting parts of a protein aggregate were determined in wild type (WT) and A53T α-synuclein (αS) oligomers, amyloids and in the complex of thymosin-β4–cytoplasmic domain of stabilin-2 (Tβ4-stabilin CTD). A53T αS aggregates have more extensive βsheet contents reflected by constant regions at low potential barriers in difference (to monomers) melting diagrams (MDs). Energies of the intermolecular interactions and of secondary structures bonds, formed during polymerization, fall into the 5.41 kJ mol−1 ≤ Ea ≤ 5.77 kJ mol−1 range for αS aggregates. Monomers lose more mobile hydration water while forming amyloids than oligomers. Part of the strong mobile hydration water–protein bonds break off and these bonding sites of the protein form intermolecular bonds in the aggregates. The new bonds connect the constituting proteins into aggregates. Amyloid–oligomer difference MD showed an overall more homogeneous solvent accessible surface of A53T αS amyloids. From the comparison of the nominal sum of the MDs of the constituting proteins to the measured MD of the Tβ4-stabilin CTD complex, the number of intermolecular bonds connecting constituent proteins into complex is 20(1) H2O/complex. The energies of these bonds are in the 5.40(3) kJ mol−1 ≤ Ea ≤ 5.70(5) kJ mol−1 range.

On the Estimation of the Molecular Inaccessible Volume and the Molecular Accessible Surface of a Ligand in Protein Ligand Systems

<p> In this work, a novel approach is proposed based on the accurate computation of a protein’s inaccessible volume as regards to a ligand, plus the corresponding surface area, where the ligand can be placed in order to “touch” the protein without any overlaps. The proposed approach can be thought as an extension of the widely used concept of the Solvent-Accessible Surface Area (SASA), evaluating the surface generated by the ligand while being rolled over all the atoms of the protein without penetrating them. Identification of the inaccessible volume of each candidate protein-ligand pair is also provided in the context of this study, along with the boundary surface where the ligand can be placed so as to be in “contact” with the protein, which is expected to significantly enhance the ability to investigate specific protein drug interactions.</p>

On the Estimation of the Molecular Inaccessible Volume and the Molecular Accessible Surface of a Ligand in Protein Ligand Systems

<p> In this work, a novel approach is proposed based on the accurate computation of a protein’s inaccessible volume as regards to a ligand, plus the corresponding surface area, where the ligand can be placed in order to “touch” the protein without any overlaps. The proposed approach can be thought as an extension of the widely used concept of the Solvent-Accessible Surface Area (SASA), evaluating the surface generated by the ligand while being rolled over all the atoms of the protein without penetrating them. Identification of the inaccessible volume of each candidate protein-ligand pair is also provided in the context of this study, along with the boundary surface where the ligand can be placed so as to be in “contact” with the protein, which is expected to significantly enhance the ability to investigate specific protein drug interactions.</p>

On the Estimation of the Molecular Inaccessible Volume and the Molecular Accessible Surface of a Ligand in Protein Ligand Systems

<p> In this work, a novel approach is proposed based on the accurate computation of a protein’s inaccessible volume as regards to a ligand, plus the corresponding surface area, where the ligand can be placed in order to “touch” the protein without any overlaps. The proposed approach can be thought as an extension of the widely used concept of the Solvent-Accessible Surface Area (SASA), evaluating the surface generated by the ligand while being rolled over all the atoms of the protein without penetrating them. Identification of the inaccessible volume of each candidate protein-ligand pair is also provided in the context of this study, along with the boundary surface where the ligand can be placed so as to be in “contact” with the protein, which is expected to significantly enhance the ability to investigate specific protein drug interactions.</p>