Using the Unfolded State as the Reference State Improves the Performance of Statistical Potentials

AbstractDistance-dependent statistical potentials are an important class of energy functions extensively used in modeling protein structures and energetics. These potentials are obtained by statistically analyzing the proximity of atoms in all combinatorial amino-acid pairs in proteins with known structures. In model evaluation, the statistical potential is usually subtracted by the value of a reference state for better selectivity. An ideal reference state should include the general chemical properties of polypeptide chains so that only the unique factors stabilizing the native structures are retained after calibrating on reference state. However, reference states available as of this writing rarely model specific chemical constraints of peptide bonds and therefore poorly reflect the behavior of polypeptide chains. In this work, we proposed a statistical potential based on unfolded state ensemble (SPOUSE), where the reference state is summarized from the unfolded state ensembles of proteins produced according to the statistical coil model. Due to its better representation of the features of polypeptides, SPOUSE outperforms three of the most widely used distance-dependent potentials not only in native conformation identification, but also in the selection of close-to-native models and correlation coefficients between energy and model error. Furthermore, SPOUSE shows promising possibility of further improvement by integration with the orientation-dependent side-chain potentials

The Mechanism of Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels Based on Molecular Dynamics Simulation

AbstractVoltage-gated sodium (Nav) channels and their Na+/K+ selectivity are of great importance in the mammalian neuronal signaling. According to mutational analysis, the Na+/K+ selectivity in mammalian Nav channels is mainly determined by the Lys and Asp/Glu residues located at the constriction site within the selectivity filter. Despite successful molecular dynamics simulations conducted on the prokaryotic Nav channels, the lack of Lys at the constriction site of prokaryotic Nav channels limits how much can be learned about the Na+/K+ selectivity in mammalian Nav channels. In this work, we modeled the mammalian Nav channel by mutating the key residues at the constriction site in a prokaryotic Nav channel (NavRh) to its mammalian counterpart. By simulating the mutant structure, we found that the Na+ preference in mammalian Nav channels is collaboratively achieved by the deselection from Lys and the selection from Asp/Glu within the constriction site

Diagnostic Value of CT-detected Extramural Vessel Invasion in Lymph Node Metastasis of Gastric Cancer

Objective: To investigate the diagnostic value of extramural vessel invasion (EMVI) in multidetector row computed tomography (MDCT) of lymph node metastasis of gastric cancer. Methods: A total of 105 patients with pathologically confirmed gastric cancer treated at our hospital between January 2020 and June 2022 were retrospectively collected. All patients underwent radical gastrectomy and D2 lymph node dissection within 2 weeks after the CT scan. The EMVI status of gastric cancer was evaluated on portal-phase MDCT images using a 5-point scale. According to the pathological status of lymph node metastasis, the patients were divided into lymph node and non-lymph node metastasis groups, and their clinicopathologic features were compared. We then performed a multivariate logistic regression analysis of lymph node metastasis in gastric cancer. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of CT-detected EMVI (ctEMVI) in lymph node metastasis, and the diagnostic values of ctEMVI and lymph node short diameter in lymph node metastasis were compared. Results: In the lymph node metastasis group, lymphovascular invasion, tumor size (>5 cm), ctEMVI positivity, and CT metastatic lymph node positivity accounted for 60.9% (n=39), 64.1% (n=41), 79.7% (n=51), and 56.2% (n=36) of cases, respectively. In the non-metastatic group, lymphovascular invasion, tumor size (>5 cm), ctEMVI positivity, and CT metastatic lymph node positivity accounted for 21.9% (n=9), 24.4% (n=10), 21.9% (n=9), and 19.5% (n=8), respectively. The intergroup difference was statistically significant. The multivariate logistic regression analysis showed that ctEMVI was an independent factor of lymph node metastasis. The ROC curve showed that the area under the curve of ctEMVI for diagnosing lymph node metastasis was 0.854. The sensitivity and accuracy of ctEMVI were superior to those of lymph node short diameter in the diagnosis of lymph node metastasis. Conclusion: This study found that ctEMVI was an independent factor and of great value in the diagnosis of lymph node metastasis

Consistency in Geometry Among Coronary Atherosclerotic Plaques Extracted From Computed Tomography Angiography

Background: The three-dimensional (3D) geometry of coronary atherosclerotic plaques is associated with plaque growth and the occurrence of coronary artery disease. However, there is a lack of studies on the 3D geometric properties of coronary plaques. We aim to investigate if coronary plaques of different sizes are consistent in geometric properties.Methods: Nineteen cases with symptomatic stenosis caused by atherosclerotic plaques in the left coronary artery were included. Based on attenuation values on computed tomography angiography images, coronary atherosclerotic plaques and calcifications were identified, 3D reconstructed, and manually revised. Multidimensional geometric parameters were measured on the 3D models of plaques and calcifications. Linear and non-linear (i.e., power function) fittings were used to investigate the relationship between multidimensional geometric parameters (length, surface area, volume, etc.). Pearson correlation coefficient (r), R-squared, and p-values were used to evaluate the significance of the relationship. The analysis was performed based on cases and plaques, respectively. Significant linear relationship was defined as R-squared > 0.25 and p < 0.05.Results: In total, 49 atherosclerotic plaques and 56 calcifications were extracted. In the case-based analysis, significant linear relationships were found between number of plaques and number of calcifications (r = 0.650, p = 0.003) as well as total volume of plaques (r = 0.538, p = 0.018), between number of calcifications and total volume of plaques (r = 0.703, p = 0.001) as well as total volume of calcification (r = 0.646, p = 0.003), and between the total volumes of plaques and calcifications (r = 0.872, p < 0.001). In plaque-based analysis, the power function showed higher R-squared values than the linear function in fitting the relationships of multidimensional geometric parameters. Two presumptions of plaque geometry in different growth stages were proposed with simplified geometric models developed. In the proposed models, the exponents in the power functions of geometric parameters were in accordance with the fitted values.Conclusion: In patients with coronary artery disease, coronary plaques and calcifications are positively related in number and volume. Different coronary plaques are consistent in the relationship between geometry parameters in different dimensions