Molecular force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models towards more intricate and expensive polarizable models that should allow more accurate description of molecular properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theoretical model, but to date has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small molecule structural and thermodynamic observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small molecules, dynamical properties away from ambient conditions, and possible improvements in aromatic interactions. State of the art electronic structure calculations reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be especially successful on protein-ligand binding and computational X-ray crystallography where polarization and accurate electrostatics are critical.

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Markov State Models provide a framework for understanding the fundamental states and rates in the conformational dynamics of biomolecules. We describe an improved protocol for constructing Markov State Models from molecular dynamics simulations. The new protocol includes advances in clustering, data preparation, and model estimation; these improvements lead to significant increases in model accuracy, as assessed by the ability to recapitulate equilibrium and kinetic properties of reference systems. A high-performance implementation of this protocol, provided in MSMBuilder2, is validated on dynamics ranging from picoseconds to milliseconds.

Purpose:Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology enables simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.Methods:A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study.Results:Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. We report tabulations of carrier frequency by self-identified ethnicity and disease.Conclusion:To our knowledge, this study of a large, ethnically diverse clinical sample provides the most accurate measurements to date of carrier frequencies for hundreds of recessive alleles. The study also yields information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of “racial” categories by the physician, as recommended by recent guidelines.

IMPORTANCE Screening for carrier status of a limited number of single-gene conditions is the current standard of prenatal care. Methods have become available allowing rapid expanded carrier screening for a substantial number of conditions. OBJECTIVES To quantify the modeled risk of recessive conditions identifiable by an expanded carrier screening panel in individuals of diverse racial and ethnic backgrounds and to compare the results with those from current screening recommendations. DESIGN, SETTING, AND PARTICIPANTS Retrospective modeling analysis of results between January 1, 2012, and July 15, 2015, from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. EXPOSURES Individuals were tested for carrier status for up to 94 severe or profound conditions. MAIN OUTCOMES AND MEASURES Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories; there were 11 categories with >5000 samples) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both. RESULTS The study included 346 790 individuals. Among major US racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100 000 (95% CI, 82.4-108.3 per 100 000) for Hispanic couples to 392.2 per 100 000 (95% CI, 366.3-420.2 per 100 000) for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines (Mann-Whitney P < .001). For Northern European couples, the 2 professional guidelines-based screening panels modeled 55.2 hypothetical fetuses affected per 100 000 (95% CI, 51.3-59.3 per 100 000) and the expanded carrier screening modeled 159.2 fetuses per 100 000 (95% CI, 150.4-168.6 per 100 000). Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6% (95% CI, 4%-8%) of hypothetical fetuses affected for East Asian couples to 87% (95% CI, 84%-90%) for African or African American couples. CONCLUSIONS AND RELEVANCE In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies. Prospective studies comparing current standard-of-care carrier screening with expanded carrier screening in at-risk populations are warranted before expanded screening is adopted.

Professional guidelines dictate that disease severity is a key criterion for carrier screening. Expanded carrier screening, which tests for hundreds to thousands of mutations simultaneously, requires an objective, systematic means of describing a given disease's severity to build screening panels. We hypothesized that diseases with characteristics deemed to be of highest impact would likewise be rated as most severe, and diseases with characteristics of lower impact would be rated as less severe. We describe a pilot test of this hypothesis in which we surveyed 192 health care professionals to determine the impact of specific disease phenotypic characteristics on perceived severity, and asked the same group to rate the severity of selected inherited diseases. The results support the hypothesis: we identified four “Tiers” of disease characteristics (1–4). Based on these responses, we developed an algorithm that, based on the combination of characteristics normally seen in an affected individual, classifies the disease as Profound, Severe, Moderate, or Mild. This algorithm allows simple classification of disease severity that is replicable and not labor intensive.

To identify potential therapeutic stop-gaps for SARS-CoV-2, we evaluated a library of 1,670 approved and reference compounds in an unbiased, cellular image-based screen for their ability to suppress the broad impacts of the SARS-CoV-2 virus on phenomic profiles of human renal cortical epithelial cells using deep learning. In our assay, remdesivir is the only antiviral tested with strong efficacy, neither chloroquine nor hydroxychloroquine have any beneficial effect in this human cell model, and a small number of compounds not currently being pursued clinically for SARS-CoV-2 have efficacy. We observed weak but beneficial class effects of -blockers, mTOR/PI3K inhibitors and Vitamin D analogues and a mild amplification of the viral phenotype with -agonists.

(Abstracted from JAMA 2016;316(7):734–742) As part of routine obstetrical practice, many prospective parents undergo genetic testing to detect carriers of specific inherited recessive diseases. There are recommendations provided by professional organizations to test for a limited number of individual diseases that are in part based on self-reported racial/ethnic backgrounds.