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The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is significant reduction of antibody binding strength corresponding to escape, the omicron spike pays a cost in terms of weaker receptor binding. The furin cleavage domain is the same or weaker binding than the alpha variant, suggesting less viral load and disease intensity than the extant delta variant.

We employ all-atom structure-based models with a force field with multiple energetic basins for the C-terminal (residues 166-226) of the mammalian prion protein. One basin represents the known alpha-helical (αH) structure while the other represents the same residues in a left-handed beta-helical (LHBH) conformation. The LHBH structure has been proposed to help describe one class of in vitro grown fibrils, as well as possibly self-templating the conversion of normal cellular prion protein to the infectious form. Yet, it is unclear how the protein may make this global rearrangement. Our results demonstrate that the conformation changes are not strongly limited by large-scale geometry modification and that there may exist an overall preference for the LHBH conformation. Furthermore, our model presents novel intermediate trapping conformations with twisted LHBH structure.

Uridine 5′-diphosphate-N-acetylglucosamine (UDP-GlcNAc) acyltransferase (LpxA) catalyzes a reversible reaction for adding anO-acyl group to the GlcNAc in UDP-GlcNAc in the first step of lipid A biosynthesis. Lipid A constitutes a major component of lipopolysaccharides, also referred to as endotoxins, which form the outer monolayer of the outer membrane of Gram-negative bacteria. Ligand-free and UDP-GlcNAc-bound crystal structures of LpxA fromBacteroides fragilisNCTC 9343, the most common pathogenic bacteria found in abdominal abscesses, have been determined and are presented here. The enzyme crystallizes in a cubic space group, with the crystallographic threefold axis generating the biological functional homotrimer and with each monomer forming a nine-rung left-handed β-helical (LβH) fold in the N-terminus followed by an α-helical motif in the C-terminus. The structure is highly similar to LpxA from other organisms. Yet, despite sharing a similar LβH structure with LpxAs fromEscherichia coliand others, previously unseen calcium ions are observed on the threefold axis inB. fragilisLpxA to help stabilize the trimeric assembly.

In the study of matter, both living and inanimate, the breakthrough discoveries and most scientists' intellectual obsessions often flow from what we call emergent behavior: phenomena not readily predictable from a detailed knowledge of the material subunits alone. We call systems that display emergent behavior complex adaptive matter, and their relevant organizing principles are unique to their scales of length and time. This issue of MRS Bulletin provides an overview of the aggregate of research on complex adaptive matter through a survey of five examples, ranging from intrinsically disordered electron matter in high-temperature superconductors to protein aggregates in amyloid diseases like Alzheimer's. We explain the philosophy and motivation for this research, noting that the study of emergent phenomena complements a globally reductionist scientific approach by seeking to identify, with intellectual precision, the relevant organizing principles governing the behavior. Our authors focus on the character of emergence for their particular systems, the role of materials research approaches to the problems, and the efforts to identify the organizing principles at work.

Many of the key challenges and opportunities in the study of matter involve complex and collective phenomena in which many parts exhibit organization without a central instruction set or clock. At the core of this enterprise in the study of matter is the search for an understanding of “emergent behavior”—that is, phenomena whose ultimate cause involves interactions between many simple units but which cannot be easily predicted from knowledge of the component parts alone. Examples of emergence are ordered convection cells in fluids, metabolic processes in cells, cognition, and stripes in superconductors. Our shorthand designation for soft, hard, and living matter exhibiting emergent behavior is “complex adaptive matter.”

We present a coarse-grained two dimensional mechanical model for the microtubule-tau bundles in neuronal axons in which we remove taus, as can happen in various neurodegenerative conditions such as Alzheimer's disease, tauopathies, and chronic traumatic encephalopathy. Our simplified model includes (i) taus modeled as entropic springs between microtubules, (ii) removal of taus from the bundles due to phosphorylation, and (iii) a possible depletion force between microtubules due to these dissociated phosphorylated taus. We equilibrate upon tau removal using steepest descent relaxation. In the absence of the depletion force, the transverse rigidity to radial compression of the bundle falls to zero at about 60% tau occupancy, in agreement with standard percolation theory results. However, with the attractive depletion force, spring removal leads to a first order collapse of the bundles over a wide range of tau occupancies for physiologically realizable conditions. While our simplest calculations assume a constant concentration of microtubule intercalants to mediate the depletion force, including a dependence that is linear in the detached taus yields the same collapse. Applying percolation theory to removal of taus at microtubule tips, which are likely to be the protective sites against dynamic instability, we argue that the microtubule instability can only obtain at low tau occupancy, from 0.06-0.30 depending upon the tau coordination at the microtubule tips. Hence, the collapse we discover is likely to be more robust over a wide range of tau occupancies than the dynamic instability. We suggest in vitro tests of our predicted collapse., Comment: 11 pages, 9 figures

The PI led theoretical studies of correlated hybridization in transition metal complexes, compounds, and molecules, and of electron transport in DNA associated with nanoelectronic conformations attached to gold electrodes and in the presence of DNA repair proteins.

The left-handed beta helix is an intriguing structural motif in several known proteins. We attempt to elucidate the factors that contribute to its stability with a theoretical-computational approach. Combining a novel form of coarse-grained molecular dynamics with parallel tempering affords access to the regime of equilibration in short peptides. For example, this method has been used to reproduce important features of the helix-coil transition in polyalanine.Three-layered beta-helical fragments are formed from various sequences that are superposed upon two backbone templates taken from sections of ideal type-I and type-II beta helices. Native, native-like, and various homogeneous sequences are simulated and their stability analyzed relative to the initial structure.An all-atom potential energy and associated parameters drawn from the Assisted Model-Building and Energy Refinement package with slight modifications. The effects of aqueous solvent are treated with the generalized Born model and a recently-proposed hydrophobic potential of mean force. Larger conformational changes can be explored by treating non-bonded forces according to Brownian dynamics while simultaneously maintaining molecular geometry with a separate algorithm.

We propose models for in vitro grown mammalian prion protein fibrils based upon left handed beta helices formed both from the N-terminal and C-terminal regions of the proteinase resistant infectious prion core. The C-terminal threading onto a beta-helical structure is almost uniquely determined by fixing the cysteine disulfide bond on a helix corner. In comparison to known left handed helical peptides, the resulting model structures have similar stability attributes including relatively low root mean square deviations in all atom molecular dynamics, substantial side-chain-to-side-chain hydrogen bonding, good volume packing fraction, and low hydrophilic/hydrophobic frustration. For the N-terminus, we propose a new threading of slightly more than two turns, which improves upon the above characteristics relative to existing three turn beta-helical models. The N-terminal and C-terminal beta helices can be assembled into eight candidate models for the fibril repeat units, held together by large hinge (order 30 residues) domain swapping, with three amenable to fibril promoting domain swapping via a small (five residue) hinge on the N-terminal side. Small concentrations of the metastable C-terminal beta helix in vivo might play a significant role in templating the infectious conformation and in enhancing conversion kinetics for inherited forms of the disease and explain resistance (for canines) involving hypothesized coupling to the methionine 129 sulfur known to play a role in human disease.

We combine molecular dynamics simulations and density functional theory to analyze the electrical structure and transmission probability in four different DNA sequences under physiological conditions. The conductance in these sequences is primarily controlled by interstrand and intrastrand coupling between low-energy guanine orbitals. Insertion of adenine-thymine base pairs between the guanine-cytosine rich domains acts as a tunneling barrier. Our theory explains recent length dependent conductance data for individual DNA molecules in water.

The mechanism of site-specific recognition of DNA by proteins has been a long-standing issue. The DNA glycosylase MutY, for instance, must find the rare 8-oxoguanine-adenine mismatches among the large number of basepairs in the DNA. This protein has a [4Fe-4S] cluster, which is highly conserved in species as diverse as Escherichia Coli and Homo sapiens. The mixed-valent nature of this cluster suggests that charge transfer may play a role in MutY's function. We have studied the energetics of the charge transfer in Bacillus stearothermophilus MutY-DNA complex using multiscale calculation including density functional theory and molecular dynamics. The [4Fe-4S] cluster in MutY is found to undergo 2+ to 3+ oxidation when coupling to DNA through hole transfer, especially when MutY is near an oxoguanine modified base (oxoG). Employing the Marcus theory for electron transfer, we find near optimal Frank-Condon factors for electron transfer from MutY to oxoguanine modified base. MutY has modest selectivity for oxoguanine over guanine due to the difference in oxidation potential. The tunneling matrix element is significantly reduced with the mutation R149W, whereas the mutation L154F reduces the tunneling matrix element as well as the Frank-Condon factor. Both L154F and R149W mutations are known to dramatically reduce or eliminate repair efficiency. We suggest a scenario where the charge transfer leads to a stabilization of the specific binding conformation, which is likely the recognition mode, thus enabling it to find the damaged site efficiently.

We apply local orbital basis density functional theory (using SIESTA) coupled with a mapping to the Anderson impurity model to estimate the Coulomb assisted or correlated hybridization between transition metal d-orbitals and ligand sp-orbitals for a number of molecular complexes. We find remarkably high values which can have several physical implications including: (i) renormalization of effective single band or multiband Hubbard model parameters for the cuprates and, potentially, elemental iron, and (ii) spin polarizing molecular transistors., Comment: 5 pages, 2 figures and 1 table included, final version as published

We present a model intended for rapid sampling of ground and excited state potential energy surfaces for first-row transition metal active sites. The method is computationally inexpensive and is suited for dynamics simulations where (1) adiabatic states are required "on-the-fly" and (2) the primary source of the electronic coupling between the diabatic states is the perturbative spin-orbit interaction among the 3d electrons. The model Hamiltonian we develop is a variant of the Anderson impurity model and achieves efficiency through a physically motivated basis set reduction based on the large value of the d-d Coulomb interaction U_{d} and a Lanczos matrix diagonalization routine to solve for eigenvalues. The model parameters are constrained by fits to the partial density of states (PDOS) obtained from ab initio density functional theory calculations. For a particular application of our model we focus on electron-transfer occuring between cobalt ions solvated by ammonium, incorporating configuration interaction between multiplet states for both metal ions. We demonstrate the capability of the method to efficiently calculate adiabatic potential energy surfaces and the electronic coupling factor we have calculated compares well to previous calculations and experiment., revtex4, 11 pages, 8 figures, submitted to J. Chem. Phys

We present a theory of nonequilibrium long range charge transfer between donor and acceptor centers in a model polymer mediated by magnetic exciton (Kondo) bound states. Our model produces electron tunneling lengths easily exceeding 10 A, as observed recently in DNA and organic charge transfer systems. This long ranged tunneling is effective for weak to intermediate donor-bridge coupling, and is enhanced both by weak to intermediate strength Coulomb hole-electron attraction (through the orthogonality catastrophe) and by coupling to local vibrational modes.

The left-handed β-helix (LHBH) is an intriguing, rare structural pattern in polypeptides that has been implicated in the formation of amyloid aggregates. We used accurate all-atom replica-exchange molecular dynamics (REMD) simulations to study the relative stability of diverse sequences in the LHBH conformation. Ensemble-average coordinates from REMD served as a scoring criterion to identify sequences and threadings optimally suited to the LHBH, as in a fold recognition paradigm. We examined the repeatability of our REMD simulations, finding that single simulations can be reliable to a quantifiable extent. We find expected behavior for the positive and negative control cases of a native LHBH and intrinsically disordered sequences, respectively. Polyglutamine and a designed hexapeptide repeat show remarkable affinity for the LHBH motif. A structural model for misfolded murine prion protein was also considered, and showed intermediate stability under the given conditions. Our technique is found to be an effective probe of LHBH stability, and promises to be scalable to broader studies of this and potentially other novel or rare motifs. The superstable character of the designed hexapeptide repeat suggests theoretical and experimental follow-ups.