CodonBERT large language model for mRNA vaccines.

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties, including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs, which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods, including on a new flu vaccine data set.

Conotoxin Prediction: New Features to Increase Prediction Accuracy.

Conotoxins are toxic, disulfide-bond-rich peptides from cone snail venom that target a wide range of receptors and ion channels with multiple pathophysiological effects. Conotoxins have extraordinary potential for medical therapeutics that include cancer, microbial infections, epilepsy, autoimmune diseases, neurological conditions, and cardiovascular disorders. Despite the potential for these compounds in novel therapeutic treatment development, the process of identifying and characterizing the toxicities of conotoxins is difficult, costly, and time-consuming. This challenge requires a series of diverse, complex, and labor-intensive biological, toxicological, and analytical techniques for effective characterization. While recent attempts, using machine learning based solely on primary amino acid sequences to predict biological toxins (e.g., conotoxins and animal venoms), have improved toxin identification, these methods are limited due to peptide conformational flexibility and the high frequency of cysteines present in toxin sequences. This results in an enumerable set of disulfide-bridged foldamers with different conformations of the same primary amino acid sequence that affect function and toxicity levels. Consequently, a given peptide may be toxic when its cysteine residues form a particular disulfide-bond pattern, while alternative bonding patterns (isoforms) or its reduced form (free cysteines with no disulfide bridges) may have little or no toxicological effects. Similarly, the same disulfide-bond pattern may be possible for other peptide sequences and result in different conformations that all exhibit varying toxicities to the same receptor or to different receptors. We present here new features, when combined with primary sequence features to train machine learning algorithms to predict conotoxins, that significantly increase prediction accuracy.

Integrative structural studies of the SARS-CoV-2 spike protein during the fusion process (2022).

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and catastrophic, worldwide health and economic impacts. The spike protein on the viral surface is responsible for viral entry into the host cell. The binding of spike protein to the host cell receptor ACE2 is the first step leading to fusion of the host and viral membranes. Despite the vast amount of structure data that has been generated for the spike protein of SARS-CoV-2, many of the detailed structures of the spike protein in different stages of the fusion pathway are unknown, leaving a wealth of potential drug-target space unexplored. The atomic-scale structure of the complete S2 segment, as well as the complete fusion intermediate are also unknown and represent major gaps in our knowledge of the infectious pathway of SAR-CoV-2. The conformational changes of the spike protein during this process are similarly not well understood. Here we present structures of the spike protein at different stages of the fusion process. With the transitions being a necessary step before the receptor binding, we propose sites along the transition pathways as potential targets for drug development.

Conformational control via sequence for a heteropeptoid in water: coupled NMR and Rosetta modelling.

We report a critical advance in the generation and characterization of peptoid hetero-oligomers. A library of sub-monomers with amine and carboxylate side-chains are combined in different sequences using microwave-assisted synthesis. Their sequence-structure propensity is confirmed by circular dichroism, and conformer subtypes are enumerated by NMR. Biasing the ψ-angle backbone to trans (180°) in Monte Carlo modelling favors i to i + 3 naphthyl-naphthyl stacking, and matches experimental ensemble distributions. Taken together, high-yield synthesis of heterooligomers and NMR with structure prediction enables rapid determination of sequences that induce secondary structural propensities for predictive design of hydrophilic peptidomimetic foldamers and their future libraries.

Modeling the Influenza A NP-vRNA-Polymerase Complex in Atomic Detail.

Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop.

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Structural Transition and Antibody Binding of EBOV GP and ZIKV E Proteins from Pre-Fusion to Fusion-Initiation State.

Membrane fusion proteins are responsible for viral entry into host cells—a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion-initiation structures, and, despite differences in viral genomes and disease etiology, many fusion proteins are arranged as trimers. Structural information for both pre-fusion and fusion-initiation states is critical for understanding virus neutralization by the host immune system. In the case of Ebola virus glycoprotein (EBOV GP) and Zika virus envelope protein (ZIKV E), pre-fusion state structures have been identified experimentally, but only partial structures of fusion-initiation states have been described. While the fusion-initiation structure is in an energetically unfavorable state that is difficult to solve experimentally, the existing structural information combined with computational approaches enabled the modeling of fusion-initiation state structures of both proteins. These structural models provide an improved understanding of four different neutralizing antibodies in the prevention of viral host entry.

Equilibrium Denaturation and Preferential Interactions of an RNA Tetraloop with Urea.

Urea is an important organic cosolute with implications in maintaining osmotic stress in cells and differentially stabilizing ensembles of folded biomolecules. We report an equilibrium study of urea-induced denaturation of a hyperstable RNA tetraloop through unbiased replica exchange molecular dynamics. We find that, in addition to destabilizing the folded state, urea smooths the RNA free energy landscape by destabilizing specific configurations, and forming favorable interactions with RNA nucleobases. A linear concentration-dependence of the free energy (m-value) is observed, in agreement with the results of other RNA hairpins and proteins. Additionally, analysis of the hydrogen-bonding and stacking interactions within RNA primarily show temperature-dependence, while interactions between RNA and urea primarily show concentration-dependence. Our findings provide valuable insight into the effects of urea on RNA folding and describe the thermodynamics of a basic RNA hairpin as a function of solution chemistry.

Free-energy landscape of a hyperstable RNA tetraloop.

We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the free-energy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the left-handed Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.

Psychologists in medical schools and academic medical centers: over 100 years of growth, influence, and partnership.

Psychologists have served on the faculties of medical schools for over 100 years. Psychologists serve in a number of different roles and make substantive contributions to medical schools' tripartite mission of research, education, and clinical service. This article provides an overview of the history of psychologists' involvement in medical schools, including their growing presence in and integration with diverse departments over time. We also report findings from a survey of medical school psychologists that explored their efforts in nonclinical areas (i.e., research, education, administration) as well as clinical endeavors (i.e., assessment, psychotherapy, consultation). As understanding of the linkage between behavioral and psychological factors and health status and treatment outcomes increases, the roles of psychologists in health care are likely to expand beyond mental health. An increasing focus on accountability-related to treatment outcomes and interprofessional research, education, and models of care delivery-will likely provide additional opportunities for psychologists within health care and professional education. The well-established alignment of psychologists' expertise and skills with the mission and complex organizational needs of medical schools augurs a partnership on course to grow stronger. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Board certification in psychology: insights from medicine and hospital psychology.

For physicians board certification is an accepted tradition that research suggests improves services and outcomes. In contrast, relatively few psychologists pursue board certification suggesting ambivalence or limited contingencies reinforcing it. The authors report on medical school and hospital-based psychologists' attitudes toward board certification and current certification status. About one-fifth (21.7%) of the sample were certified by the American Board of Professional Psychology, a greater proportion than psychologists generally: Highest rates were seen in neuropsychology (7.5%), clinical psychology (6.4%), clinical child and adolescent psychology (3.2%) and clinical health psychology (2.8%). Few (<2%) reported their hospitals required board certification. Half recognized benefits to the profession for psychologists pursuing board certification, yet 70% opposed requiring it for their hospital-based practice. Forces seeking to promote healthcare quality ultimately may increase expectations for board certification. If consumers, employers, hospitals and managed care organizations demand board certification for health professionals, greater numbers of psychologists would likely seek it.

Hospital privileges for psychologists in the era of competencies and increased accountability.

After campaigning to be granted hospital privileges decades ago, new issues are emerging that are affecting psychologists' hospital privileges. Some of the forces shaping hospital privileges emanate from within the field of psychology, where there has been a movement to more closely examine psychologists' competences. Other forces impinging on hospital privileges are external to psychology, most notably the Joint Commission, which has promulgated new standards for hospital-based practitioners across disciplines. This article discusses the effects of these new standards on the practice of psychology and describes the findings of a survey examining how privileges are currently obtained and maintained within hospitals.