Comparative assessment of differently randomized accelerated particle swarm optimization and squirrel search algorithms for selective harmonics elimination problem.

A random initialization of the search particles is a strong argument in favor of the deployment of nature-inspired metaheuristic algorithms when the knowledge of a good initial guess is lacked. This article analyses the impact of the type of randomization on the working of algorithms and the acquired solutions. In this study, five different types of randomizations are applied to the Accelerated Particle Swarm Optimization (APSO) and Squirrel Search Algorithm (SSA) during the initializations and proceedings of the search particles for selective harmonics elimination (SHE). The types of randomizations include exponential, normal, Rayleigh, uniform, and Weibull characteristics. The statistical analysis shows that the type of randomization does impact the working of optimization algorithms and the fittest value of the objective function.

SHP-1 tyrosine phosphatase binding to c-Src kinase phosphor-dependent conformations: A comparative structural framework.

SHP-1 is a cytosolic tyrosine phosphatase that is primarily expressed in hematopoietic cells. It acts as a negative regulator of numerous signaling pathways and controls multiple cellular functions involved in cancer pathogenesis. This study describes the binding preferences of SHP-1 (pY536) to c-Srcopen (pY416) and c-Srcclose (pY527) through in silico approaches. Molecular dynamics simulation analysis revealed more conformational changes in c-Srcclose upon binding to SHP-1, as compared to its active/open conformation that is stabilized by the cooperative binding of the C-SH2 domain and C-terminal tail of SHP-1 to c-Src SH2 and KD. In contrast, c-Srcclose and SHP-1 interaction is mediated by PTP domain-specific WPD-loop (WPDXGXP) and Q-loop (QTXXQYXF) binding to c-Srcclose C-terminal tail residues. The dynamic correlation analysis demonstrated a positive correlation for SHP-1 PTP with KD, SH3, and the C-terminal tail of c-Srcclose. In the case of the c-Srcopen-SHP-1 complex, SH3 and SH2 domains of c-Srcopen were correlated to C-SH2 and the C-terminal tail of SHP-1. Our findings reveal that SHP1-dependent c-Src activation through dephosphorylation relies on the conformational shift in the inhibitory C-terminal tail that may ease the recruitment of the N-SH2 domain to phosphotyrosine residue, resulting in the relieving of the PTP domain. Collectively, this study delineates the intermolecular interaction paradigm and underlying conformational readjustments in SHP-1 due to binding with the c-Src active and inactive state. This study will largely help in devising novel therapeutic strategies for targeting cancer development.

Structural basis of Klotho binding to VEGFR2 and TRPC1 and repurposing calcium channel blockers as TRPC1 antagonists for the treatment of age-related cardiac hypertrophy.

Cardiac hypertrophy results in the higher rate of heart failures among aged groups. Klotho is an anti-aging protein that is involved in the regulation of VEGF-mediated Ca2+ entry by direct interaction with Vascular endothelial growth factor receptor 2 (VEGFR2) and transient receptor potential canonical Ca2+ channel 1 (TRPC1). Here, in this study, through in silico analysis, we modeled TRPC1 3-dimensional structure and followed by its optimization, characterized the interaction pattern of TRPC1, Klotho and VEGFR2. Subsequent molecular dynamics (MD) simulation analysis revealed that Klotho-specific (P520-N630) region exhibited interaction with VEGFR2, while its C-terminal region (I822-A931) demonstrated binding to the 3rd extracellular loop of TRPC1 that is adjacent to pore region. Through TRPC1 homotetramer formation, the residues in the periphery of pore region were carefully evaluated. In order to scrutinize known Ca2+ channel blockers for their ability to bind at the pore region of TRPC1, 31 known compounds were tested through docking runs and three hits, named as diltiazem impurity B (b3), diltiazem (b5) and felodipine (b6) were selected for detailed binding analysis through MD runs. Evidently, inhibitor-bound TRPC1 pore area was more constricted (8.6 Å2, 25.1 Å2 and 18.8 Å2, respectively) than apo-TRPC1 (60 Å2). These findings suggest that Ca+2 channel blockers may serve as promising agents to impair the TRPC1 functional store-operated calcium channel (SOCC) activity in the old patients lacking Klotho expression. Thus, pore region of homotetrameric TRPC1 may be blocked via repurposing of known Ca+2 blockers to antagonize TRPC signaling for the treatment of cardiac hypertrophy.

Molecular dynamics and structural analysis of the binding of COP1 E3 ubiquitin ligase to ß-catenin and TRIB pseudokinases.

Tribbles pseudokinases, Tribbles homolog 1 (TRIB1), Tribbles homolog 2 (TRIB2), and Tribbles homolog 3 (TRIB3), bind to constitutive photomorphogenesis protein 1 (COP1) E3 ligase to mediate the regulation of ß-catenin expression. The interaction mechanism between COP1 E3 ligase and ß-catenin has not been addressed to date. Based on the functional presence of TRIBs in wingless-related integration site (WNT) signaling, we analyzed their interaction patterns with ß-catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and ß-catenin. TRIB1 (355-DQIVPEY-361), TRIB2 (326-DQLVPDV-332), and TRIB3 (333-AQVVPDG-339) peptides revealed a shallow binding pocket at the COP1 interface to accommodate the V-P sequence motif. Reinvigoration of the comparative binding pattern and subtle structural analysis via docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, topological, and tunnel analysis revealed that both ß-catenin phosphodegron (DSGXXS) and TRIB (D/E/AQXVPD/E) motifs occupied a common COP1 binding site. Current study suggests a structural paradigm of TRIB homologs bearing a conserved motif that may compete with ß-catenin phosphodegron signature for binding to WD40 domain of COP1. Thorough understanding of the structural basis for TRIB-mediated regulation of WNT/ß-catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers.

Impact of parameter control on the performance of APSO and PSO algorithms for the CSTHTS problem: An improvement in algorithmic structure and results.

Cascaded Short Term Hydro-Thermal Scheduling problem (CSTHTS) is a single objective, non-linear multi-modal or convex (depending upon the cost function of thermal generation) type of Short Term Hydro-Thermal Scheduling (STHTS), having complex hydel constraints. It has been solved by many metaheuristic optimization algorithms, as found in the literature. Recently, the authors have published the best-achieved results of the CSTHTS problem having quadratic fuel cost function of thermal generation using an improved variant of the Accelerated PSO (APSO) algorithm, as compared to the other previously implemented algorithms. This article discusses and presents further improvement in the results obtained by both improved variants of APSO and PSO algorithms, implemented on the CSTHTS problem.

Evidence for NAD+-dependent histone dynamics and tunneling associated conformational transitions in circadian deacetylase SIRT1.

Circadian rhythm is a biological cycle that is involved in all processes over 24 h day and night period. Sirtuin 1 (SIRT1) is a 747 amino acid-long class III Nicotinamide adenine dinucleotide (NAD+)-dependent histone that acts as a circadian deacetylase. Here we present a detailed in-silico analysis to address comparative structure-function relationship and interaction pattern of SIRT1-NAD+/Zn+2 and SIRT1NAD+/Zn+2-acetylated histone H4 (H4KAC16) complexes. MD-based ensemble analysis suggested an overall loss of helical content (21.144-17.230%) in H4KAC16-bound SIRT1NAD+/Zn+2 due to conformational readjustments of 32 residues, as compared to SIRT1NAD+/Zn+2. Due to increased flexibility, SIRT1-specific SER275, SER442 and ARG466 residues involved in NAD+ association facilitated in the formation of a transient tunnel (17.77 Å) that was further elongated to 19.25 Å upon SIRT1NAD+/Zn+2 binding to H4KAC16. A close conformation of SIRT1NAD+/Zn+2 was achieved due to binding of H4KAC16 that results in the movement of helical module towards Zn+2 binding module together with Rossmann fold at NAD+ binding region. Furthermore, a 2-fold increase (4.31-8.82 Å) in the measured inter-atomic distance between imidazole nitrogen of conserved HIS363 and NAD+-specific 2'-hydroxyl group of ribose ring was evident in SIRT1NAD+/Zn+2-H4KAC16 complex. At 90 ns time scale, the distance between C6A of adenine ring and C2N of nicotinamide ring was more extended (19.32 Å) in SIRT1NAD+/Zn+2-H4KAC16 as compared to SIRT1NAD+/Zn+2 (11.54 Å). These data suggest that H4KAC16 binding to SIRT1 may coordinate an unusual conformational readjustment of nicotinamide ring at site-b and reposition of HIS363 to facilitate SIRT1-dependent deacetylase activity. Taken together, our findings will help in understanding the precise structural changes occurring in response to SIRT1 deacetylase activity of core histone.

Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors.

P21-activated kinases (PAKs) are serine/threonine protein kinases that are subdivided into two groups on the basis of their domain architecture: group-I (PAK1-3) and group-II (PAK4-6). PAKs are considered as attractive drug targets that play vital role in cell proliferation, survival, motility, angiogenesis and cytoskeletal dynamics. In current study, molecular dynamics simulation-based comparative residual contributions and differential transitions were monitored in both active and inactive states of human PAK homologs for therapeutic intervention. Due to their involvement in cancer, infectious diseases, and neurological disorders, it is inevitable to develop novel therapeutic strategies that specifically target PAKs on the basis of their activity pattern. In order to isolate novel inhibitors that are able to bind at the active sites of PAK1 and PAK4, high throughput structure-based virtual screening was performed. Multiple lead compounds were proposed on the basis of their binding potential and targeting region either phosphorylated (active) or unphosphorylated PAK isoform (inactive). Thus, ATP-competitive inhibitors may prove ideal therapeutic choice against PAK family members. The detailed conformational readjustements occurring in the PAKs upon phosphorylation-dephosphorylation events may serve as starting point for devising novel drug molecules that are able to target on activity basis. Overall, the observations of current study may add valuable contribution in the inventory of novel inhibitors that may serve as attractive lead compounds for targeting PAK family members on the basis of activity-based conformational changes.

Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding.

Klotho is an anti-aging protein that is engaged in the suppression of canonical WNT signaling. In this study, we investigated the expression pattern of human WNTs and Klotho in the pancreatic cancer. In the cancerous cells, WNT-1 exhibited much higher expression as compared to other WNTs, while no WNT expression was detected in the normal tissue. In contrast, Klotho expression was significantly low in the cancerous tissue. Based on these observations, we intended to explore Klotho binding to WNT-1 and cystein-rich domains (CRDs) of Frizzled (FZD) homologs through molecular docking and dynamics simulation assays. Interestingly, similar region of WNT-1 was detected in binding with Klotho and CRDs of FZD-1/2. FZD-CRDs were grasped by the association of peripheral hydrophobic residues of WNT-1 U-shaped cavity. Subsequently, WNT-1-bound Klotho-peptides were isolated and reevaluated for their binding abilities against WNT-1 and FZD-CRDs., The conformational readjustements of these complexes were deeply analyzed by calculating the size of WNT-1 U-shaped cavity. In comparison to apo-WNT-1, cavity opening was markedly enhanced (8.2 Što 15.64 Å, 32.89 Šand 35.11 Å) in WNT-1-a, WNT-1-c and WNT-1-e complexes, respectively. Thus Klotho-derived peptides may facilitate distinct conformational changes in the WNT-1-FZD associated region. As a result, aberrant loss of FZD binding may lead to augment WNT signaling. Overall, current study opens up new avenues in the pancreatic cancer therapeutics through antagonizing WNT-1 by Klotho.

Interactive structural analysis of ßTrCP1 and PER2 phosphoswitch binding through dynamics simulation assay.

Circadian rhythm is rhythmic gene expression that is involved in various processes of life over a day and night cycle. The rhythmic sleep disorders arise due to misalignment of sleep-wake cycle influenced by phosphorylation of PERIOD2 (PER2) phosphodegron (SSGYGS), the conserved interaction site of ß-transducin repeat-containing protein (ßTrCP1). Here, we employed in silico approach to study the interaction pattern of ßTrCP1 with PER2WT, PER2SER480ALA and PER2SER484ALA phosphodegron peptides. Substitution of phosphorylatable SER480 or SER484 into ALA resulted in the shifting of PER2 phosphodegron binding at the lower face of ß-propeller, by involvement of both SER residues. PER2 binding at the shallow cavity of ßTrCP1 induced conformational readjustment in ARG524 residue that connected the upper hemisphere base (10.5 Å) with the roof of lower hemisphere (6.6 Å) to create a uniform tunnel-like structure. In the absence of phosphorylation, PER2 and ßTrCP1 binding stability may be compromised resulting in the enhancement of PER2 level in the cytoplasm that may disrupt circadian clock and aging. Taken together, this study will help in understanding the structural basis of conserved phosphoswitch mechanism in the mammalian circadian oscillation.

Targeted inhibition of Klotho binding to fibroblast growth factor 23 prevents hypophosphetemia.

Klotho is a transmembrane protein which plays significant role in the pathogenesis of phosphate ion (Pi)-related disorders. Pi accumulation in human kidney tissues results in the major metabolic disorders due to malfunctioning of Klotho-FGFR1-FGF23 trimeric complex. The potential role of Klotho in Pi metabolism was elaborated through modeling and interaction analysis of glycosyl hydrolase (GS1 and GS2) domains with Fibroblast growth factor 23 (FGF23). In order to inhibit the association of Klotho and FGF23, binding patterns of three reported hits (N-(2-chlorophenyl)-1H-indole-3-carboxamide, N-[2-(1-cyclohexen-1-yl)ethyl]-6,7,8,9-tetrahydropyrido[1,2-e]purin-4-amine and 2-(1-propyl)amino-11-chlorothiazolo[5,4-a]acridine) were evaluated through molecular docking analysis. These inhibitors effectively targeted both GS1 and GS2 domains of Klotho at the similar sites required for FGF23 binding. To further characterize the comparative binding profile of these compounds, molecular dynamics simulation assays were performed. Taken together, current study emphasizes that Klotho may be anticipated as a target molecule in familial hypophosphatemic rickets and mentioned compounds may prove to be effective therapeutic targets against hypophosphetemia induced disorders.