No abstract

QM/MM simulations have become an indispensable tool in many chemical and biochemical investigations. Considering the tremendous degree of success, including recognition by a 2013 Nobel Prize in Chemistry, are there still “burning challenges” in QM/MM methods, especially for biomolecular systems? In this short Perspective, we discuss several issues that we believe greatly impact the robustness and quantitative applicability of QM/MM simulations to many, if not all, biomolecules. We highlight these issues with observations and relevant advances from recent studies in our group and others in the field. Despite such limited scope, we hope the discussions are of general interest and will stimulate additional developments that help push the field forward in meaningful directions.

Purpose The purpose of this study was to determine whether susceptibility tensor imaging (STI) could overcome limitations of current techniques to detect tubules throughout the kidney. Methods Normal mouse kidneys (n=4) were imaged at 9.4T using a 3D gradient multiecho sequence (55-micron isotropic resolution). Phase images from 12 orientations were obtained to compute the susceptibility tensor. Diffusion tensor imaging (DTI) with 12 encoding directions was compared with STI. Tractography was performed to visualize and track the course of tubules with DTI and STI. Confocal microscopy was used to identify which tubular segments of the nephron were detected by DTI and STI. Results Diffusion anisotropy was limited to the inner medulla of the kidney. DTI did not find a significant number of coherent tubular tracks in the outer medulla or cortex. With STI, we found strong susceptibility anisotropy and many tracks in the inner and outer medulla, and in limited areas of the cortex. Conclusion STI was able to track tubules throughout the kidney, while DTI was limited to the inner medulla. STI provides a novel contrast mechanism related to local tubule microstructure and may offer a powerful method to study the nephron.

Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.