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Recent years have witnessed an explosion in computational power, leading to attempts to model ever more complex systems. Nevertheless, there remain cases for which the use of brute-force computer simulations is clearly not the solution. In such cases, great benefit can be obtained from the use of physically sound simplifications. The introduction of such coarse graining can be traced back to the e
In recent years, the EVB has become a widely used tool in the QM/MM modeling of reactions in condensed phases and in biological systems, with ever increasing popularity. However, despite the fact that its power and validity have been repeatedly established since 1980, a recent work (Valero, R.; et al. J. Chem. Theory Comput. 2009, 5, 1) has strongly criticized this approach, while not discussing t
Oxyanion holes play a major role in catalyzing enzymatic reactions, yet the corresponding energetics is frequently misunderstood. The main problem may be associated with the nontrivial nature of the electrostatic preorganization effect, without following the relevant formulation. That is, although the energetics of oxyanion holes have been fully quantified in early studies (which include both the
Enzymes play a key role in almost all biological processes, accelerating a variety of metabolic reactions as well as controlling energy transduction, the transcription, and translation of genetic information, and signaling. They possess the remarkable capacity to accelerate reactions by many orders of magnitude compared to their uncatalyzed counterparts, making feasible crucial processes that woul
Phosphate hydrolysis is ubiquitous in biology. However, despite intensive research on this class of reactions, the precise nature of the reaction mechanism remains controversial. Herein, we have examined the hydrolysis of three homologous phosphate diesters. The solvation free energy was simulated by means of either an implicit solvation model (COSMO), hybrid quantum mechanical/molecular mechanica
The idea that enzymes catalyze reactions by dynamical coupling between the conformational motions and the chemical coordinates has recently attracted major experimental and theoretical interest. However, experimental studies have not directly established that the conformational motions transfer energy to the chemical coordinate, and simulating enzyme catalysis on the relevant timescales has been i
DNA polymerases make up a family of enzymes responsible for regulating DNA replication and repair, which in turn maintains the integrity of the genome. However, despite intensive kinetic, crystallographic, and computational studies, elucidation of the detailed enzymatic mechanism still presents a significant challenge. We recently developed an alternative strategy for exploring the fidelity and me
Phosphate monoester and anhydride hydrolysis is ubiquitous in biology, being involved in, amongst other things, signal transduction, energy production, and the regulation of protein function. Therefore, this reaction has understandably been the focus of intensive research. Nevertheless, the precise mechanism by which phosphate monoester hydrolysis proceeds remains controversial. Traditionally, it
Many phosphatases make use of metal ions to aid catalysis of phosphate ester hydrolysis. Here, we investigate the impact of metal ions on the potential energy surface (PES), and hence the preferred reaction mechanism, for a simple model for hydrolysis of phosphate ester monoanions. We show that, while both associative (A(N) + D(N)) and dissociative (D(N) + A(N)) mechanisms are represented on the p
The hydrolysis of phosphate esters is crucially important to biological systems, being involved in, among other things, signaling, energy transduction, biosynthesis, and the regulation of protein function. Despite this, there are many questions that remain unanswered in this important field, particularly with regard to the preferred mechanism of hydrolysis of phosphate esters, which can proceed th
Hybrid quantum mechanical/molecular mechanical (QM/MM) approaches have been used to provide a general scheme for chemical reactions in proteins. However, such approaches still present a major challenge to computational chemists, not only because of the need for very large computer time in order to evaluate the QM energy but also because of the need for proper computational sampling. This review fo
Phosphate ester hydrolysis is ubiquitous in biology, playing a central role in energy production, signaling, biosynthesis, and the regulation of protein function among other things. Although the mechanism of action of the enzymes regulating this reaction has been the focus of intensive research in the past few decades, the correct description of this apparently simple reaction remains controversia
Protein tyrosine phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of
Targeted molecular dynamics was used to examine the mechanism of WPD loop closure in PTP1B, which is essential for the activity of the enzyme. Two important regions are identified: the R-loop (residues 113-118), which assists in substrate binding, and the S-loop (residues 198-209), which undergoes a conformational change that appears to be vital for the movement of the WPD loop. The S-loop is adja
Non-islet cell tumor hypoglycemia (NICTH) is one of the paraneoplastic syndromes manifesting severe hypoglycemia caused by aberrant production of high-molecular-weight insulin-like growth factor 2 (big-IGF2). Two surgical cases of extremely large thoracic solitary fibrous tumors (SFT) with unusual history of NICTH are presented. One case manifested severe hypoglycemia after four years of the first
BACKGROUND: Tumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II.CASE PRESENTATION: Here, we report the case of a 62-year-old woman who presented with an abdominal ma
BACKGROUND: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no stand
BACKGROUND: SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other c
BACKGROUND AND AIM: This study aimed to clarify the efficacy and safety of 48-week pemafibrate treatment in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) complicated by dyslipidemia.METHODS: A total of 110 patients diagnosed with MASLD complicated by dyslipidemia received pemafibrate at a dose of 0.1 mg twice daily for 48 weeks.RESULTS: The participants were 54 mal
OBJECTIVE: Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with bot
