Search

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features in simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations with only a modest increase in cost.

AmberTools is a free and open-source collection of programs used to set up, run, and analyze molecular simulations. The newer features contained within AmberTools23 are briefly described in this Application note.

Competing Interests: Disclaimer: The contents of this article are solely the views of the authors and do not necessarily represent the official views of The Coalition for Physician Accountability or the Undergraduate Medical Education to Graduate Medical Education Review Committee.

Introduction: The Association of American Medical Colleges (AAMC) proposed thirteen core Entrustable Professional Activities (EPAs) that all graduates should be able to perform under indirect supervision upon entering residency. As an underlying premise is that graduates ready to do so will be better prepared to transition to the responsibilities of residency, we explored the relationship between postgraduate year (PGY)-1 residents' self-assessed preparedness to perform core EPAs under indirect supervision at the start of residency with their ease of transition to residency., Methods: Using response data to a questionnaire administered in September 2019 to PGY-1 residents who graduated from AAMC core EPA pilot schools, we examined between-group differences and independent associations for each of PGY-1 position type, specialty, and "EPA-preparedness" score (proportion of EPAs the resident reported as prepared to perform under indirect supervision at the start of residency) and ease of transition to residency (from 1 = much harder to 5 = much easier than expected)., Results: Of 274 questionnaire respondents (19% of 1438 graduates), 241 (88% of 274) had entered PGY-1 training and completed all questionnaire items of interest. EPA-preparedness score (mean 0.71 [standard deviation 0.26]) correlated with ease of transition (3.1 [0.9]; correlation = .291, p  < .001). In linear regression controlling for specialty (among other variables), EPA-preparedness score ( β -coefficient 1.08; 95% confidence interval .64-1.52; p  < .001) predicted ease of transition to residency., Conclusion: Graduates who felt prepared to perform many of the core EPAs under indirect supervision at the start of PGY-1 training reported an easier-than-expected transition to residency., Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-021-01370-3., Competing Interests: Conflict of InterestThe authors are all directly involved in the Core EPA pilot in various roles. Three authors are employed by the organization (AAMC) that convened the Core EPA pilot; the remaining five authors are faculty at medical schools participating in the core EPAs for entering residency pilot and are involved in core EPA implementation at their respective schools. The authors declare no competing interests., (© International Association of Medical Science Educators 2021.)

Attitudes toward interprofessional education are positive overall, but inferences about its key elements are hard to draw. Studies with qualitative strands examining interprofessional education's key elements (communication, collaboration/teamwork, learning in practice, and understanding of roles) are especially needed. This mixed quantitative/qualitative standardized patient simulation involved 10 family nurse practitioner and 10 medical students. Both cohorts expressed improved teamwork confidence but were concerned about the complexity of teamwork and pressures on communication. At the complexity/communication nexus, nurse practitioner students thought interprofessional trust and equality were key; medical students saw the importance of strategizing multiple professional perspectives.

The ability to effectively work in interprofessional teams is listed as one of the five core competencies in health professions education. Though the importance of interprofessional education (IPE) has been established, results of studies have been difficult to compare due to the high variability of programs. We undertook a scoping review to examine the use of a prescribed curriculum, TeamSTEPPS, in IPE. Articles describing TeamSTEPPS implementations were extracted from Pubmed, Embase, and Scopus. Studies with two or more health professions students reporting on a clear evaluation and published in English were eligible for inclusion. Two researchers independently applied inclusion criteria to studies and reconciled conflicts for a final selection. The reference lists of selected papers were also searched for relevant studies. Data were extracted from each of the articles independently using a standard form. Twenty-four papers describing 23 unique programs were included. Programs used a variety of teaching modalities and included students from two to ten health professions, most commonly medical and nursing students. Programs used a range (n = 11) of validated IPE evaluation surveys, few of which were part of the TeamSTEPPS program. Methods included multimodal evaluations, self-assessment confidence and attitude surveys, pre/post-test models, and external evaluation of simulation performance. There was great variation in the implementation of TeamSTEPPS implying that while a consistent curriculum it can be adapted to meet the needs of different educational contexts. The variation in evaluation methods makes comparing and synthesis of results problematic. Future IPE research can expand on the use of this prescribed curriculum, especially with focus on uniform evaluation methods.

Ionizable residues in the interior of proteins play essential roles, especially in biological energy transduction, but are relatively rare and seem incompatible with the complex and polar environment. We perform a comprehensive study of the internal ionizable residues on 21 variants of staphylococcal nuclease with internal Lys, Glu, or Asp residues. Using pH replica exchange molecular dynamics simulations, we find that, in most cases, the pK a values of these internal ionizable residues are shifted significantly from their values in solution. Our calculated results are in excellent agreement with the experimental observations of the Garcia-Moreno group. We show that the interpretation of the experimental pK a values requires the study of not only protonation changes but also conformational changes. The coupling between the protonation and conformational equilibria suggests a mechanism for efficient pH-sensing and regulation in proteins. This study provides new physical insights into how internal ionizable residues behave in the hydrophobic interior of proteins.

OpenMM is a molecular dynamics simulation toolkit with a unique focus on extensibility. It allows users to easily add new features, including forces with novel functional forms, new integration algorithms, and new simulation protocols. Those features automatically work on all supported hardware types (including both CPUs and GPUs) and perform well on all of them. In many cases they require minimal coding, just a mathematical description of the desired function. They also require no modification to OpenMM itself and can be distributed independently of OpenMM. This makes it an ideal tool for researchers developing new simulation methods, and also allows those new methods to be immediately available to the larger community.

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields.

We evaluate the performance of the automated fragmentation quantum mechanics/molecular mechanics approach (AF-QM/MM) on the calculation of protein and nucleic acid NMR chemical shifts. The AF-QM/MM approach models solvent effects implicitly through a set of surface charges computed using the Poisson-Boltzmann equation, and it can also be combined with an explicit solvent model through the placement of water molecules in the first solvation shell around the solute; the latter substantially improves the accuracy of chemical shift prediction of protons involved in hydrogen bonding with solvent. We also compare the performance of AF-QM/MM on proteins and nucleic acids with two leading empirical chemical shift prediction programs SHIFTS and SHIFTX2. Although the empirical programs outperform AF-QM/MM in predicting chemical shifts, the differences are in some cases small, and the latter can be applied to chemical shifts on biomolecules which are outside the training set employed by the empirical programs, such as structures containing ligands, metal centers, and non-standard residues. The AF-QM/MM described here is implemented in version 5 of the SHIFTS software, and is fully automated, so that only a structure in PDB format is required as input.

Unlabelled: Tumor endothelial marker 1 (TEM1, endosialin) is a tumor vascular marker with significant diagnostic and therapeutic potential. However, in vivo small animal models to test affinity reagents specifically targeted to human (h)TEM1 are limited. We describe a new mouse tumor model where tumor vascular endothelial cells express hTEM1 protein., Methods: Immortalized murine endothelial cells MS1 were engineered to express hTEM1 and firefly luciferase and were inoculated in nude mice either alone, to form hemangioma-like endothelial grafts, or admixed with ID8 ovarian tumor cells, to form chimeric endothelial-tumor cell grafts. MORAb-004, a monoclonal humanized IgG 1 antibody specifically recognizing human TEM1 was evaluated for targeted theranostic applications, i.e., for its ability to affect vascular grafts expressing hTEM1 as well as being a tool for molecular positron emission tomography (PET) imaging., Results: Naked MORAb-004 treatment of mice bearing angioma grafts or chimeric endothelial-tumor grafts significantly suppressed the ability of hTEM1-positive endothelial cells, but not control endothelial cells, to form grafts and dramatically suppressed local angiogenesis. In addition, highly efficient radioiodination of MORAb-004 did not impair its affinity for hTEM1, and [ (124)I]-MORAb-004-PET enabled non-invasive visualization of tumors enriched with hTEM1-positive, but not hTEM1 negative vasculature with high degree of specificity and sensitivity., Conclusion: The development of a new robust endothelial graft model expressing human tumor vascular proteins will help accelerate the development of novel theranostics targeting the tumor vasculature, which exhibit affinity specifically to human targets but not their murine counterparts. Our results also demonstrate the theranostic potential of MORAb-004 as PET imaging tracer and naked antibody therapy for TEM1-positive tumor.

Emerging antibiotic resistance may be slowed through effective implementation of treatment guidelines. Our case-control study showed that providers who treated gonorrhea differently from guidelines in Massachusetts accounted for approximately 4% of cases and were associated with private practice/health maintenance organization settings and lower-incidence locations. Patient β-lactam allergy was also significantly associated with guideline nonadherence.

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.

The Legionella pneumophila protein RalF is secreted into host cytosol via the Dot/Icm type IV transporter where it acts to recruit ADP-ribosylation factor (Arf) to pathogen-containing phagosomes in the establishment of a replicative organelle. The presence in RalF of the Sec7 domain, present in all Arf guanine nucleotide exchange factors, has suggested that recruitment of Arf is an early step in pathogenesis. We have determined the crystal structure of RalF and of the isolated Sec7 domain and found that RalF is made up of two domains. The Sec7 domain is homologous to mammalian Sec7 domains. The C-terminal domain forms a cap over the active site in the Sec7 domain and contains a conserved folding motif, previously observed in adaptor subunits of vesicle coat complexes. The importance of the capping domain and of the glutamate in the "glutamic finger," conserved in all Sec7 domains, to RalF functions was examined using three different assays. These data highlight the functional importance of domains other than Sec7 in Arf guanine nucleotide exchange factors to biological activities and suggest novel mechanisms of regulation of those activities.