Molecular Dynamics Simulations

Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia patients. The first five approved BCR::ABL1 TKIs target the ATP-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe...

The plastic response of the Senkov HfNbTaTiZr high-entropy alloy is explored by means of simulated nanoindentation tests. Both a random alloy and an alloy with chemical short-range order are investigated and compared to the well understood case of an elementary Ta crystal. Strong differences in the dislocation plasticity between the alloys and the elementary Ta crystal are found. The high-entropy alloys show only little relaxation of the indentation dislocation network after indenter retraction and only negligible dislocation emission into the sample interior...

Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution...

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds...

In this paper, we have performed an all-atom molecular dynamics simulation to understand the structure and dynamics of Na+ ions in water mixed Ionic liquids (Water in Ionic liquid). Two ionic liquid (IL) systems consist of (1) 1-butyl-3-methylimidazolium [BMIM] tetrafluoroborate [BF4 ] and (2) 1-butyl-3-methylimidazolium [BMIM] hexafluorophosphate [PF6 ] were considered in this work. We understand various inter- molecular structures and dynamic and thermodynamic behaviours of Na+ ions in the water- mixed IL systems...

Type 2 diabetes mellitus (T2DM) has become a serious public health problem both in our country and worldwide, being the most prevalent type of diabetes. The combined use of drugs in the treatment of T2DM leads to serious side effects, including gastrointestinal problems, liver toxicity, hypoglycemia, and treatment costs. Hence, there has been a growing emphasis on drugs that demonstrate dual interactions. Several studies have suggested that dual-target agents for peroxisome proliferator-activated receptor-γ (PPAR-γ) and alpha-glucosidase (α-glucosidase) could be a potent approach for treating patients with diabetes...

A quantum chemistry (QC)/molecular dynamics (MD) scheme is developed to calculate electronic properties of semiconducting polymers in three steps: (i) constructing the polymer force field through a unified workflow, (ii) equilibrating polymer models, and (iii) calculating electronic structure properties (e.g., density of states and localization length) from the equilibrated models by QC approaches. Notably, as the second step of this scheme is generally the most time-consuming one, we introduce an alternative method to compute thermally averaged electronic properties in bulk, based on the simulation of a polymer chain in the solution of its repeat units, which is shown to reproduce the microstructure of polymer chains and their electrostatic effect (successfully tested for five benchmark polymers) 10 times faster than state-of-the-art methods...

Simulating the quantum dynamics of molecules in the condensed phase represents a longstanding challenge in chemistry. Trapped-ion quantum systems may serve as a platform for the analog-quantum simulation of chemical dynamics that is beyond the reach of current classical-digital simulation. To identify a 'quantum advantage' for these simulations, performance analysis of both analog-quantum simulation on noisy hardware and classical-digital algorithms is needed. In this Review, we make a comparison between a noisy analog trapped-ion simulator and a few choice classical-digital methods on simulating the dynamics of a model molecular Hamiltonian with linear vibronic coupling...

BACKGROUND: Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5)...

HYPOTHESIS: Graphene quantum dots (GQDs) with various functional groups are hypothesized to inhibit the α-synuclein (αS) dimerization, a crucial step in Parkinson's disease pathogenesis. The potential of differently functionalized GQDs is systematically explored. EXPERIMENTS: All-atom replica-exchange molecular dynamics simulations (accumulating to 75.6 μs) in explicit water were performed to study the dimerization of the αS non-amyloid component region and the influence of GQDs modified with various functional groups...

Polypropylene (PP) and polystyrene (PS) underwent a comprehensive investigation into their mechanical and chemical degradation through reactive molecular dynamics simulations. The simulations utilized the ReaxFF force field for CHO (carbon-hydrogen-oxygen) systems in the combustion branch. The study included equilibrium simulations to determine densities and melting temperatures, non-equilibrium simulations for stress-strain and Young moduli determination, mechanical cleaving to identify surface species resulting from material fragmentation, and shock compression simulations to elucidate chemical reactions activated by some external energy sources...

Preserving the genomic integrity stands a fundamental necessity, primarily achieved by the DNA repair proteins through their continuous patrolling on the DNA in search of lesions. However, comprehending how even a single base-pair lesion can be swiftly and specifically recognized amidst millions of base-pair sites remains a formidable challenge. In this study, we employ extensive molecular dynamics simulations using an appropriately tuned model of both protein and DNA to probe the underlying molecular principles...

The kinesin-5 family member, Eg5, plays very important role in the mitosis. As a mitotic protein, Eg5 is the target of various mitotic inhibitors. There are two targeting pockets in the motor domain of Eg5, which locates in the α2/L5/α3 region and the α4/α6 region respectively. We investigated the interactions between the different inhibitors and the two binding pockets of Eg5 by using all-atom molecular dynamics method. Combined the conformational analysis with the free-energy calculation, the binding patterns of inhibitors to the two binding pockets are shown...

In transdermal drug delivery system (TDDS) patches, achieving prolonged adhesion, high drug loading, and rapid drug release simultaneously presented a significant challenge. In this study, a PHT-SP-Cu2+ adhesive was synthesized using polyethylene glycol (PEG), hexamethylene diisocyanate (HDI), trimethylolpropane (TMP), and silk protein (SP) as functional monomers which were combined with Cu2+ to improve the adhesion, drug loading, and drug release of the patch. The structure of the adhesion chains and the formation of Cu2+ -p-π conjugated network in PHT-SP-Cu2+ were characterized and elucidated using different characterization methods including FT-IR, 13 C NMR, XPS, SEM imaging and thermodynamic evaluation...

The Fragile X messenger ribonucleoprotein (FMRP) is a complex, multi-domain protein involved in interactions with various macromolecules, including proteins and coding/non-coding RNAs. The three KH domains (KH0, KH1 and KH2) within FMRP are recognized for their roles in mRNA binding. In the context of Fragile X syndrome (FXS), over-and-above CGG triplet repeats expansion, three specific point mutations have been identified, each affecting one of the three KH domains (R138 QKH0, G266 EKH1, and I304N KH2) resulting in the expression of non-functional FMRP...

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated...

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy...

Gallium arsenide (GaAs) materials have the advantages of high electron mobility, electron saturation drift rate, and other irreplaceable semiconducting properties. They play an important role in the electronics, solar and other fields. However, during GaAs film sedimentary growth, As atoms can undergo segregation to form As8 clusters because of the influence of external factors, which affect the surface morphology and internal structure of these films. In this study, a series of investigations on the deposition and growth of GaAs crystal films were performed...

ORF3b is one of the SARS-CoV-2 accessory proteins. Previous experimental study suggested that ORF3b prevents IRF3 translocating to nucleus. However, the biophysical mechanism of ORF3b-IRF3 interaction is elusive. Here, we explored the conformation ensemble of ORF3b using all-atom replica exchange molecular dynamics simulation. Disordered ORF3b has mixed α-helix, β-turn and loop conformers. The potential ORF3b-IRF3 binding modes were searched by docking representative ORF3b conformers with IRF3, and 50 ORF3b-IRF3 complex poses were screened using molecular dynamics simulations ranging from 500 to 1000 ns...

Understanding the formation of β-fibrils over the gold surface is of paramount interest in nano-bio-medicinal Chemistry. The intricate mechanism of self-assembly of neurofibrillogenic peptides and their growth over the gold surface remains elusive, as experiments are limited in unveiling the microscopic dynamic details, in particular, at the early stage of the peptide aggregation. In this work, we carried out equilibrium molecular dynamics and enhanced sampling simulations to elucidate the underlying mechanism of the growth of an amyloid-forming sequence of tau fragments over the gold surface...