Muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin. Direct characterization of how small changes in the myosin–actin complex impact its force production remains challenging. Molecular dynamics (MD) simulations, although capable of studying protein structure–function relationships, are limited owing to the slow timescale of the myosin cycle as well as a lack of various intermediate structures for the actomyosin complex. Here, employing comparative modeling and enhanced sampling MD simulations, we show how the human cardiac myosin generates force during the mechanochemical cycle. Initial conformational ensembles for different myosin–actin states are learned from multiple structural templates with Rosetta. This enables us to efficiently sample the energy landscape of the system using Gaussian accelerated MD. Key myosin loop residues, whose substitutions are related to cardiomyopathy, are identified to form stable or metastable interactions with the actin surface. We find that the actin-binding cleft closure is allosterically coupled to the myosin motor core transitions and ATP-hydrolysis product release from the active site. Furthermore, a gate between switch I and switch II is suggested to control phosphate release at the prepowerstroke state. Our approach demonstrates the ability to link sequence and structural information to motor functions.
Ovarian cancer mortality is on the rise in China. Surgery followed by adjuvant chemotherapy is the most extensively used treatment for tumour recovery. An excellent nutritional condition prior and throughout treatment serves to improve the quality of life and, as a result, the treatment result. The goal of this research was how diet affected the functioning standard of those living in carcinoma who were receiving postoperative treatment. BMI was utilised to evaluate nutrition, accompanied by albuminemia, prealbuminemia, and serum C-reactive protein, that is used to evaluate excessive catabolism. The QLQ-C30 questionnaire assessed standard of living. The performance status of the patient is decided with the help of the WHO performance scale for cancer patients. The study identified the statistically significant relationship between the performance status and hypercatabolism in the global health (quality of life) of the patient. While body mass index is often considered as a standard for assessment of nutritional status, it has affected only the cognitive function of the patient. In this study, we have concluded that in addition to direct measurement of the BMI, other clinical parameters such as serum CRP should be considered to get a better outcome of chemotherapy.
Muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin. Direct characterization of how small changes in the myosin-actin complex impact its force production remains challenging. Molecular dynamics (MD) simulations, although capable of studying protein structure-function relationships, are limited owing to the slow timescale of the myosin cycle as well as a lack of various intermediate structures for the actomyosin complex. Here, employing comparative modeling and enhanced sampling MD simulations, we show how the human cardiac myosin generates force during the mechanochemical cycle. Initial conformational ensembles for different myosin-actin states are learned from multiple structural templates with Rosetta. This enables us to efficiently sample the energy landscape of the system using Gaussian accelerated MD. Key myosin loop residues, whose substitutions are related to cardiomyopathy, were identified to form stable or transient interactions with the actin surface. We find that the actin-binding cleft closure and lever arm swing are allosterically coupled to the myosin core transitions and products release from the active site. Furthermore, a gate between switch I and switch II is suggested to control phosphate release at the pre-powerstroke state. Our approach demonstrates the ability to link sequence and structural information to motor functions.
The long-term goal of the proposed research is to characterize the function of the motif (''M-domain'') of cardiac myosin binding protein C (cMyBP-C) in damping spontaneous oscillatory contractions (SPOC) in skinned cardiomyocytes. The motif aids in binding of cMyBP-C to both myosin and actin, and changes to its phosphorylation affect cMyBP-C affinity for both. Reduced phosphorylation of the motif is common in many cases of hypertrophic cardiomyopathy (HCM), and cMyBP-C mutations that reduce cMyBP-C expression are present in approximately 50% of cases of HCM. Recently, we developed a new ''cut-and-paste'' method that allows sequential removal of domains C0-C7 (including the M-domain) and covalent replacement with any desired recombinant protein containing SpyCatcher (SC). Using this new method we found that acute removal of cMyBP-C domains C0-C7 resulted in the appearance of SPOC in Ca 2þ activated skinned cardiomyocytes, whereas covalent replacement with recombinant C0-C7-SC domains damped SPOC. Here we tested whether the motif is necessary to damp SPOC when C0-C7-SC is added back by comparing C0-C7-SC that contains motif and C0-C7DM-SC that lacks the motif. Results showed that C0-C7DM-SC did not damp SPOC, implicating the motif as a critical domain in regulating the process of SPOC. Ongoing studies will investigate additional cMyBP-C recombinant protein constructs to determine whether the motif alone is sufficient to damp SPOC and whether phosphorylation of the motif affects cMyBP-C's capability to damp SPOC. This work is supported by NIH HL080367 and HL140925 and Interdisciplinary Training in Cardiovascular Research T32HL007249.
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