Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces.

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here, we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2 [hACE2]) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild-type strain. Our key findings are that glycans play a vital role at the RBD···hACE2 interface for the Omicrons, and the interplay between glycans and sequence mutations leads to enhanced binding. We find significant structural differences in the complexes, which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild-type. However, further differences between subvariants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: mutations reduce interdomain interactions between the up chain and its clockwise neighbor chain in particular for the latter, resulting in enhanced flexibility for BA.2. Consequently, we see occurrence of additional close contacts in one replica of BA.2, which include binding to hACE2 by a second RBD in addition to the up chain. Although this motif is not seen in BA.1, we find that the Omicrons can directly/indirectly bind a down-RBD to hACE2 through glycans: the role of the glycan on N90 of hACE2 switches from inhibiting to facilitating the binding to Omicron spike protein via glycan-protein lateral interactions. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

Aggregation Behavior of Model Asphaltenes Revealed from Large-Scale Coarse-Grained Molecular Simulations.

Fully atomistic simulations of models of asphaltenes in simple solvents have allowed the study of trends in aggregation phenomena to understand the underlying role played by molecular structure. The detail included at this scale of molecular modeling is, however, at odds with the required spatial and temporal resolution needed to fully understand asphaltene aggregation. The computational cost required to explore the relevant scales can be reduced by employing coarse-grained (CG) models, which consist of lumping a few atoms into a single segment that is characterized by effective interactions. In this work, CG force fields developed via the statistical associating fluid theory (SAFT-γ) [ Müller , E. A. ; Jackson , G. Annu. Rev. Chem. Biomol. Eng. 5 , 2014 , 405 - 427 ] equation of state (EoS) provide a reliable pathway to link the molecular description with macroscopic thermophysical data. A recent modification of the SAFT-VR EoS [ Müller , E. A. ; Mejía , A. Langmuir 33 , 2017 , 11518 - 11529 ], which allows for the parameterization of homonuclear rings, is selected as the starting point to develop CG models for polycyclic aromatic hydrocarbons. The new aromatic-core models, along with others published for simpler organic molecules, are adopted for the construction of asphaltene models by combining different chemical moieties in a group-contribution fashion. We apply the procedure to two previously reported asphaltene models and perform molecular dynamics simulations to validate the coarse-grained representation against benchmark systems of 27 asphaltenes in a pure solvent (toluene or heptane) described in a fully atomistic fashion. An excellent match between both levels of description is observed for the cluster size, radii of gyration, and relative-shape-anisotropy-factor distributions. We exploit the advantages of the CG representation by simulating systems containing up to 2000 asphaltene molecules in an explicit solvent investigating the effect of asphaltene concentration, solvent composition, and temperature on aggregation. By studying large systems facilitated by the use of CG models, we observe stable continuous distributions of molecular aggregates at conditions away from the two-phase precipitation point. As a further example application, a widely accepted interpretation of cluster-size distributions in asphaltenic systems is challenged by performing system-size tests, reversibility checks, and a time-dependence analysis. The proposed coarse-graining procedure is seen to be general and predictive and, hence, can be applied to other asphaltenic molecular structures.

SAFT-γ Force Field for the Simulation of Molecular Fluids. 5. Hetero-Group Coarse-Grained Models of Linear Alkanes and the Importance of Intramolecular Interactions.

The SAFT-γ Mie group-contribution equation of state [ Papaioannou J. Chem. Phys. 2014 , 140 , 054107 ] is used to develop a transferable coarse-grained (CG) force-field suitable for the molecular simulation of linear alkanes. A heterogroup model is fashioned at the resolution of three carbon atoms per bead in which different Mie (generalized Lennard-Jones) interactions are used to characterize the terminal (CH3-CH2-CH2-) and middle (-CH2-CH2-CH2-) beads. The force field is developed by combining the SAFT-γ CG top-down approach [ Avendaño J. Phys. Chem. B 2011 , 115 , 11154 ], using experimental phase-equilibrium data for n-alkanes ranging from n-nonane to n-pentadecane to parametrize the intermolecular (nonbonded) bead-bead interactions, with a bottom-up approach relying on simulations based on the higher resolution TraPPE united-atom (UA) model [ Martin ; , Siepmann J. Phys. Chem. B 1998 , 102 , 2569 ] to establish the intramolecular (bonded) interactions. The transferability of the SAFT-γ CG model is assessed from a detailed examination of the properties of linear alkanes ranging from n-hexane ( n-C6H14) to n-octadecane ( n-C18H38), including an additional evaluation of the reliability of the description for longer chains such as n-hexacontane ( n-C60H122) and a prototypical linear polyethylene of moderate molecular weight ( n-C900H1802). A variety of structural, thermodynamic, and transport properties are examined, including the pair distribution functions, vapor-liquid equilibria, interfacial tension, viscosity, and diffusivity. Particular focus is placed on the impact of incorporating intramolecular interactions on the accuracy, transferability, and representability of the CG model. The novel SAFT-γ CG force field is shown to provide a reliable description of the thermophysical properties of the n-alkanes, in most cases at a level comparable to the that obtained with higher resolution models.

Monte Carlo simulation of flexible trimers: from square well chains to amphiphilic primitive models.

In this work, we present Monte Carlo computer simulation results of a primitive model of self-assembling system based on a flexible 3-mer chain interacting via square-well interactions. The effect of switching off the attractive interaction in an extreme sphere is analyzed, since the anisotropy in the molecular potential promotes self-organization. Before addressing studies on self-organization it is necessary to know the vapor liquid equilibrium of the system to avoid to confuse self-organization with phase separation. The range of the attractive potential of the model, λ, is kept constant and equal to 1.5σ, where σ is the diameter of a monomer sphere, while the attractive interaction in one of the monomers was gradually turned off until a pure hard body interaction was obtained. We present the vapor-liquid coexistence curves for the different models studied, their critical properties, and the comparison with the SAFT-VR theory prediction [A. Gil-Villegas, A. Galindo, P. J. Whitehead, S. J. Mills, G. Jackson, and A. N. Burgess, J. Chem. Phys. 106, 4168 (1997)]. Evidence of self-assembly for this system is discussed.

Evaluation of the pressure tensor and surface tension for molecular fluids with discontinuous potentials using the volume perturbation method.

In this article we apply the volume-perturbation method to systems of particles interacting via discontinuous potentials. We have found that an accurate Monte Carlo simulation protocol can be used in order to study properties of very general non-spherical systems with discontinuous potentials, such as chain molecules and spherocylinders with square-well interactions, and chain molecules with square-well and square-shoulder interactions. From the simulation results obtained for these systems we verify that: (1) the method reproduces the pressure as used in NPT simulations; (2) discontinuous infinite repulsive interactions give asymmetric contributions to the pressure when compression and expansion movements are used; however for finite interactions these contributions are symmetric; and (3) the pressure contributions preserve the additivity of the potential interactions. Density profiles and surface tension for subcritical conditions are accurately predicted.