PYSCF is a Python-based general-purpose electronic structure platform that both supports first-principles simulations of molecules and solids, as well as accelerates the development of new methodology and complex computational workflows. The present paper explains the design and philosophy behind PYSCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PYSCF as a development environment. We then summarize the capabilities of PYSCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PYSCF across the domains of quantum chemistry, materials science, machine learning and quantum information science.

Abstract-Dilated cardiomyopathy and hypertrophic cardiomyopathy (HCM) can be caused by mutations in thin filament regulatory proteins of the contractile apparatus. In vitro functional assays show that, in general, the presence of dilated cardiomyopathy mutations decreases the Ca 2ϩ sensitivity of contractility, whereas HCM mutations increase it. To assess whether this functional phenomenon was a direct result of altered Ca 2ϩ affinity or was caused by altered troponin-tropomyosin switching, we assessed Ca 2ϩ binding of the regulatory site of cardiac troponin C in wild-type or mutant troponin complex and thin filaments using a fluorescent probe (2-[4Ј-{iodoacetamido}aniline]-naphthalene-6-sulfonate) attached to Cys35 of cardiac troponin C. The Ca 2ϩ -binding affinity (pCa 50 ϭ6.57Ϯ0.03) of reconstituted troponin complex was unaffected by all of the HCM and dilated cardiomyopathy troponin mutants tested, with the exception of the troponin I Arg145Gly HCM mutation, which caused an increase (⌬pCa 50 ϭϩ0.31Ϯ0.05). However, when incorporated into regulated thin filaments, all but 1 of the 10 troponin and ␣-tropomyosin mutants altered Ca 2ϩ -binding affinity. Both HCM mutations increased Ca 2ϩ affinity (⌬pCa 50 ϭϩ0.41Ϯ0.02 and ϩ0.51Ϯ0.01), whereas the dilated cardiomyopathy mutations decreased affinity (⌬pCa 50 ϭϪ0.12Ϯ0.04 to Ϫ0.54Ϯ0.04), which correlates with our previous functional in vitro assays. The exception was the troponin T Asp270Asn mutant, which caused a significant decrease in cooperativity. Because troponin is the major Ca 2ϩ buffer in the cardiomyocyte sarcoplasm, we suggest that Ca 2ϩ affinity changes caused by cardiomyopathy mutant proteins may directly affect the Ca 2ϩ transient and hence Ca 2ϩ -sensitive disease state remodeling pathways in vivo. This represents a novel mechanism for this class of mutation.

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Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. Inherited DCM can result from mutations in the genes encoding cardiac troponin T, troponin C, and ␣-tropomyosin; different mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM, we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations in troponin T, troponin C, and ␣-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1:1 ratio of mutant/wild-type proteins (the likely in vivo ratio), all showed reduced Ca 2؉ sensitivity of activation in ATPase and motility assays, and except for one ␣-tropomyosin mutant showed lower maximum Ca 2؉ activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca 2؉ sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.

We have compared the in vitro regulatory properties of recombinant human cardiac troponin reconstituted using wild type troponin T with troponin containing the ⌬Lys-210 troponin T mutant that causes dilated cardiomyopathy (DCM) and the R92Q troponin T known to cause hypertrophic cardiomyopathy (HCM). Troponin containing ⌬Lys-210 troponin T inhibited actin-tropomyosin-activated myosin subfragment-1 ATPase activity to the same extent as wild type at pCa8.5 (>80%) but produced substantially less enhancement of ATPase at pCa4.5. The Ca 2؉ sensitivity of ATPase activation was increased (⌬pCa 50 ‫؍‬ ؉0.2 pCa units) and cooperativity of Ca 2؉ activation was virtually abolished. Equimolar mixtures of wild type and ⌬Lys-210 troponin T gave a lower Ca 2؉ sensitivity than with wild type, while maintaining the diminished ATPase activation at pCa4.5 observed with 100% mutant. In contrast, R92Q troponin gave reduced inhibition at pCa8.5 but greater activation than wild type at pCa4.5; Ca 2؉ sensitivity was increased but there was no change in cooperativity. In vitro motility assay of reconstituted thin filaments confirmed the ATPase results and moreover indicated that the predominant effect of the ⌬Lys-210 mutation was a reduced sliding speed. The functional consequences of this DCM mutation are qualitatively different from the R92Q or any other studied HCM troponin T mutation, suggesting that DCM and HCM may be triggered by distinct primary stimuli.

Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal–regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.

The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin. Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases. Various biophysical and physiological approaches have been used to investigate the structure-function effects of the mutations, and animal models developed. The reported effects of the mutations include changes to the secondary structure of tropomyosin, its binding to actin and its position on the thin filament, and alterations to actin-myosin interactions and myofilament Ca(2+) sensitivity. The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca(2+) sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca(2+) responsiveness. As well as impacting on contractility, these changes are likely to alter intracellular Ca(2+) handling and signaling, and a combination of these alterations may provide the trigger for disease remodeling.

BiographiesMaximilian Schilcher received his M.Sc. at the University of Augsburg and is currently a Ph.D. student at the Technical University of Munich. His research mainly focuses on the influence of dynamic disorder on optoelectronic properties of halide perovskites, using a combination of density functional theory and a large-scale tightbinding approach.Paul J. Robinson received his B.S. in physics from the University of California, Los Angeles, in 2018 and is currently an NSF Graduate Research Fellow at Columbia University. His research interests are focused on creating and applying new methods to describe the quantum dynamics of electron−phonon coupled materials.