Molecular dynamics (MD) simulations have become increasingly popular in studying the motions and functions of biomolecules. The accuracy of the simulation, however, is highly determined by the molecular mechanics (MM) force field (FF), a set of functions with adjustable parameters to compute the potential energies from atomic positions. However, the overall quality of the FF, such as our previously published ff99SB and ff14SB, can be limited by assumptions that were made years ago. In the updated model presented here (ff19SB), we have significantly improved the backbone profiles for all 20 amino acids. We fit coupled φ/ψ parameters using 2D φ/ψ conformational scans for multiple amino acids, using as reference data the entire 2D quantum mechanics (QM) energy surface. We address the polarization inconsistency during dihedral parameter fitting by using both QM and MM in aqueous solution. Finally, we examine possible dependency of the backbone fitting on side chain rotamer. To extensively validate ff19SB parameters, and to compare to results using other Amber models, we have performed a total of ∼5 ms MD simulations in explicit solvent. Our results show that after amino-acid-specific training against QM data with solvent polarization, ff19SB not only reproduces the differences in amino-acid-specific Protein Data Bank (PDB) Ramachandran maps better but also shows significantly improved capability to differentiate amino-acid-dependent properties such as helical propensities. We also conclude that an inherent underestimation of helicity is present in ff14SB, which is (inexactly) compensated for by an increase in helical content driven by the TIP3P bias toward overly compact structures. In summary, ff19SB, when combined with a more accurate water model such as OPC, should have better predictive power for modeling sequence-specific behavior, protein mutations, and also rational protein design. Of the explicit water models tested here, we recommend use of OPC with ff19SB.

<p>Molecular dynamics (MD) simulations have become increasingly popular in studying the motions and functions of biomolecules. The accuracy of the simulation, however, is highly determined by the molecular mechanics (MM) force field (FF), a set of functions with adjustable parameters to compute the potential energies from atomic positions. However, the overall quality of the FF, such as our previously published ff99SB and ff14SB, can be limited by assumptions that were made years ago. In the updated model presented here (ff19SB), we have significantly improved the backbone profiles for all 20 amino acids. We fit coupled ϕ/ψ parameters using 2D ϕ/ψ conformational scans for multiple amino acids, using as reference data the entire 2D quantum mechanics (QM) energy surface. We address the polarization inconsistency during dihedral parameter fitting by using both QM and MM in solution. Finally, we examine possible dependency of the backbone fitting on side chain rotamer. To extensively validate ff19SB parameters, we have performed a total of ~5 milliseconds MD simulations in explicit solvent. Our results show that after amino-acid specific training against QM data with solvent polarization, ff19SB not only reproduces the differences in amino acid specific Protein Data Bank (PDB) Ramachandran maps better, but also shows significantly improved capability to differentiate amino acid dependent properties such as helical propensities. We also conclude that an inherent underestimation of helicity is present in ff14SB, which is (inexactly) compensated by an increase in helical content driven by the TIP3P bias toward overly compact structures. In summary, ff19SB, when combined with a more accurate water model such as OPC, should have better predictive power for modeling sequence-specific behavior, protein mutations, and also rational protein design. </p>

The coronavirus disease 2019 (COVID-19) pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine development efforts are underway, there are many outstanding questions on the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and host cell entry. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular spike glycoprotein and at the receptor-binding domain (RBD)-receptor interface, suggesting a role in infection. Here, we perform explicitly solvated, all-atom, molecular dynamics simulations of the glycosylated, full-length, membrane-bound ACE2 receptor in both an apo and spike RBD-bound state to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full-length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer and suggests a mechanical contribution of the host receptor toward the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can potentially be exploited for the rational design of effective SARS-CoV-2 therapeutics.

The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we map the free energy landscape for RBD opening and identify interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.

Rechargeable lithium-ion battery technology has revolutionized energy storage for small electronic devices. However, a deeper understanding is required of the interfaces present in such devices for this technology to continue to advance. While many insights into the solid electrolyte interphase (SEI) for lithium-ion systems have been collected from decades of study, many questions also remain. In particular, this work is interested in exploring SEI composition and its impact on electrolyte structure and dynamics. By using a previously tested classical molecular dynamics approach, the impact of the crystallinity of the SEI interface as well as its content of organic and inorganic species is assessed. It is found that the presence of an amorphous SEI results in the accumulation of ions at the interface, ordering of solvent molecules, and a slowing down of solvation dynamics. These behaviors are intensified when crystal surfaces from LiF and Li2CO3 are considered. In addition to these general observations, the changes in lithium and PF6 – solvation structure are also considered as they approach the SEI interface. In both cases, the drive to aggregate arising from greater ion accumulation is shielded in part from interaction with the charged groups in the SEI interface. This competition is tilted toward salt aggregation in the case of crystalline SEI, suggesting a significantly different solvation environment than typically seen in bulk for adsorbed species.

The COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics.Statement of SignificanceAs the host receptor of SARS-CoV-2, ACE2 has been the subject of extensive structural and antibody design efforts in aims to curtail COVID-19 spread. Here, we perform molecular dynamics simulations of the homodimer ACE2 full-length structure to study the dynamics of this protein in the context of the cellular membrane. The simulations evidence exceptional plasticity in the protein structure due to flexible hinge motions in the head-transmembrane domain linker region and helix mobility in the membrane, resulting in a varied ensemble of conformations distinct from the experimental structures. Our findings suggest a dynamical contribution of ACE2 to the spike glycoprotein shedding required for infection, and contribute to the question of stoichiometry of the Spike-ACE2 complex.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The viral spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell, and is the primary target of neutralizing antibodies. However, antibody recognition often involves variable surface epitopes on the spike, and the receptor binding domain (RBD) of the spike hides from immune recognition underneath a glycan shield aside from brief dynamic excursions to search for the host-cell surface receptor ACE2. Using an atomistic model of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we identified specific interactions that stabilize the closed RBD, and mapped the free energy landscape for RBD opening. We characterized a transient pocket associated with a hinge motion during opening of the RBD, suggesting the possibility of allosteric control of the RBD via this region. Substitution of a conserved alanine to bulkier leucine in the pocket shifted the RBD equilibrium to favor the open, exposed state, as did removal of a conserved lysine that forms a critical salt-bridge in the closed, hidden state. Results from our virtual screening, MD simulations and free energy landscape calculations for wild-type spike suggest that small molecules can spontaneously bind to the highly conserved hinge pocket, and that such binding can shift the RBD equilibrium to favor the open state. Stabilizing the open state may facilitate antibody recognition by forcing the spike to expose critical RBD epitopes, and also could increase the likelihood of premature triggering of the spike fusion machinery via S1 shedding, neutralizing the infectious ability of the virus.

Reactions between carbonate electrolytes and graphite electrodes in lithium-ion storage devices produce a surface film of byproducts known as the solid electrolyte interphase (SEI). Significant progress has been made in assessing the composition and structure of these interphases; however, their impact on lithium transport during charge and discharge lacks molecular detail. Over the past decade, electrochemical impedance spectroscopy (EIS) has shown that lithium transport is limited by a combination of ion desolvation and ion conduction through the SEI, however which step is rate limiting remains unresolved. In this work, we simulate the first step in this process, i.e., ion desolvation, both into and out of two model SEI's comprised of lithium ethylene dicarbonate (LEDC) and Li 2 CO 3 interfaced with an ethylene carbonate electrolyte. By correlating free-energy changes with solvation structure, we show that the path taken for Li + insertion is a two-step mechanism consisting of overcoming two energy barriers to adsorption and then absorption. The largest measured barrier of the two is 59.2 kJ/mol, within the estimates obtained from EIS measurements. Ion extraction from the LEDC, however, follows a different free-energy profile determined by the flexibility of the surface groups to extend into the electrolyte. The dependence of extraction from LEDC on the nature of the surface groups, emphasized by comparison with ion extraction from the more rigid Li 2 CO 3 surface, highlights the complex relationship between SEI composition and lithium transport.