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Background: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population., Aims: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis., Methods: We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures., Results: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045)., Conclusion: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background/aims: Low serum testosterone is common in cirrhotic men, but the impact of disease aetiology remains uncertain. This study compares serum total testosterone (TT) levels by disease aetiology and assesses its prognostic value., Methods: Single-centre retrospective study of cirrhotic men who had TT levels measured between 2002 and 2020. A cut-off of 12 nmol/L was used to define low TT and 230 pmol/L for calculated free testosterone (cFT). Linear and logistic regression used to adjust for variables known to affect testosterone levels and assess for an association between levels and outcomes., Results: Of 766 cirrhotic men, 33.3% had alcohol-related liver disease (ALD) and 11.9% had non-alcoholic fatty liver disease (NAFLD). The median age was 56 years (interquartile range (IQR) 50-61), and the model for end-stage liver disease (MELD) score 14 (IQR 9-20). TT levels were low in 53.3% of patients, (median 11.0 nmol/L; IQR 3.7-19.8) and cFT low in 79.6% (median 122 pmol/L; IQR 48.6-212). Median TT was lower in men with ALD (7.6 nmol/L; IQR 2.1-16.2) and NAFLD (9.8 nmol/L; IQR 2.75-15.6) compared to other aetiologies (11.0 nmol/L; IQR 3.73-19.8) ( p  < 0.001 for all), which remained true after adjustment for age and MELD score. TT was inversely associated with 12-month mortality or transplant (381 events, p  = 0.02) and liver decompensation (345 events, p  = 0.004)., Conclusions: Low serum testosterone is common in cirrhotic men and is associated with adverse clinical outcomes. TT levels are significantly lower in ALD and NAFLD compared to other disease aetiologies. Further large-scale studies are required to assess the potential benefits of testosterone therapy.

Introduction: Collaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community., Areas Covered: In this paper, the MEDIATE initiative is described. This shares compounds' libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative's capacity to identify active compounds., Expert Opinion: Structure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files.

Background: Pre-transplant muscle wasting measured by computed tomography has been associated with adverse clinical outcomes after liver transplantation including increased rates of sepsis and hospitalisation days. Upper limb lean mass (LM) measured by dual-energy X-ray absorptiometry (DEXA) was recently identified as a novel predictor of sarcopenia-associated mortality in men waitlisted for transplantation., Aim: To investigate the use of DEXA LM in predicting gender-stratified early post-transplant outcomes., Methods: Liver transplant recipients who underwent pre-transplant DEXA body composition imaging between 2002 and 2017 were included. Endpoints included post-transplant mortality and graft failure, bacterial infections, acute cellular rejection (ACR) and intensive care and total hospital length of stay., Results: Four hundred and sixty-nine patients met inclusion criteria of which 338 were male (72%). Median age was 55.0 years (interquartile range 47.4, 59.7) and model for end-stage liver disease (MELD) score 16. Median time from assessment to transplantation was 7 mo (3.5, 12). Upper limb LM was inversely associated with bacterial infections at 180 d post-transplant (hazard ratio = 0.42; 95% confidence interval: 0.20-0.89; P = 0.024) in males only. There was a negative correlation between upper limb LM and intensive care (τ b = -0.090, P = 0.015) and total hospital length of stay (τ b = -0.10, P = 0.0078) in men. In women, neither MELD nor body composition parameters were associated with post-transplant adverse outcomes or increased length of stay. Body composition parameters, MELD and age were not associated with 90-d mortality or graft failure in either gender. There were no significant predictors of early ACR., Conclusion: Sarcopenia is an independent and potentially modifiable predictor of increased post-transplant bacterial infections and hospital length of stay in men with cirrhosis. DEXA upper limb LM provides a novel measure of muscle wasting that has prognostic value in this cohort. The lack of association in women requires further investigation., Competing Interests: Conflict-of-interest statement: All authors declare no conflict-of-interest related to this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in people with diabetes with no available treatment., Aim: To explore the effect of testosterone treatment on liver. Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver remains poorly studied., Methods: This secondary analysis of a 40 wk, randomised, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging (MRI)., Results: Of 88 patients enrolled in the index study, 39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo. All patients had > 5% hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD. Median liver fat at baseline was 15.0% (IQR 11.5%-21.1%) in the testosterone and 18.4% (15.0%-28.9%) in the placebo group. Median ALT was 34units/L (26-38) in the testosterone and 32units/L (25-52) in the placebo group. At week 40, patients receiving testosterone had a median reduction in absolute liver fat of 3.5% (IQR 2.9%-6.4%) compared with an increase of 1.2% in the placebo arm (between-group difference 4.7% P < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001)., Conclusion: Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone. Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified., Competing Interests: Conflict-of-interest statement: Apostolov R, Darren Wong and Numan Kutaiba have no conflicts of interest to declare. Emily Gianatti, Paul Gow and Marie Sinclair have received financial support for research from Bayer Pharma AG more than five years ago. Mathis Grossmann has received research funding from Bayer Pharma AG, Otzuka and speaker’s honoraria from Besins Health Care and Novartis., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: While clinical guidelines recommend hepatocellular carcinoma (HCC) surveillance for at-risk individuals, reported surveillance rates in the United States and Europe remain disappointingly low., Aim: To quantify HCC surveillance in an Australian cohort, and assess for factors associated with surveillance underutilisation., Methods: All patients undergoing HCC surveillance liver ultrasounds between January 1, 2018 to June 30, 2018 at a tertiary hospital in Melbourne, Australia, were followed until July 31, 2020, or when surveillance was no longer required. The primary outcome was the percentage of time up-to-date with HCC surveillance (PTUDS). Quantile regression was performed to determine the impact of factors associated with HCC surveillance underutilisation., Results: Among 775 at-risk patients followed up for a median of 27.5 months, the median PTUDS was 84.2% (IQR: 66.3%-96.3%). 85.0% of patients were followed up by specialist gastroenterologists. Amongst those receiving specialist care, quantile regression demonstrated differential associations at various quantile levels of PTUDS for several factors. Older age at the 25 th quantile (estimate 0.002 per percent, P = 0.03), and cirrhotic status at the 75 th quantile (estimate 0.021, P = 0.017), were significantly associated with greater percentage of time up-to-date. African ethnicity (estimate -0.089, P = 0.048) and a culturally and linguistically diverse (CALD) background (estimate -0.063, P = 0.01) were significantly associated with lower PTUDS at the 50 th quantile, and again for CALD at the 75 th quantile (estimate -0.026, P = 0.045)., Conclusion: While median PTUDS in this Australian cohort study was 84.2%, awareness of the impact of specific factors across PTUDS quantiles can aid targeted interventions towards improved HCC surveillance., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest or financial supports., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Management of single small hepatocellular carcinoma (HCC) is straightforward with curative outcomes achieved by locoregional therapy or resection. Liver transplantation is often considered for multiple small or single large HCC. Management of two small HCC whether presenting synchronously or sequentially is less clear., Aim: To define the outcomes of patients presenting with two small HCC., Methods: Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC ≤ 3 cm between January 2000 and March 2018. Primary outcomes were overall survival (OS) and transplant-free survival (TFS)., Results: 104 patients were identified (male n = 89). Median age was 63 years (interquartile range 58-67.75) and the most common aetiology of liver disease was hepatitis C (40.4%). 59 (56.7%) had synchronous HCC and 45 (43.3%) had sequential. 36 patients died (34.6%) and 25 were transplanted (24.0%). 1, 3 and 5-year OS was 93.0%, 66.1% and 62.3% and 5-year post-transplant survival was 95.8%. 1, 3 and 5-year TFS was 82.1%, 45.85% and 37.8%. When synchronous and sequential groups were compared, OS (1,3 and 5 year synchronous 91.3%, 63.8%, 61.1%, sequential 95.3%, 69.5%, 64.6%, P = 0.41) was similar but TFS was higher in the sequential group (1,3 and 5 year synchronous 68.5%, 37.3% and 29.7%, sequential 93.2%, 56.6%, 48.5%, P = 0.02) though this difference did not remain during multivariate analysis., Conclusion: TFS in patients presenting with two HCC ≤ 3 cm is poor regardless of the timing of the second tumor. All patients presenting with two small HCC should be considered for transplantation., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Sarcopenia, defined as loss of muscle mass, strength and function, is associated with adverse clinical outcomes in patients with cirrhosis. Despite improved understanding of the multifaceted pathogenesis, there are few established therapies to treat or prevent muscle loss in this population. This narrative review examines the available literature investigating the role of nutraceuticals for the prevention or treatment of muscle wasting in chronic liver disease., Methods: A comprehensive search or Medline and PubMED databases was conducted. Reference lists were screened to identify additional articles., Results: A number of nutritional supplements and vitamins target the specific metabolic derangements that contribute to sarcopenia in cirrhosis including altered amino acid metabolism, hyperammonaemia and inflammation. Branched chain amino acid (BCAA) supplementation has proposed anabolic effects through dual pathways of enhanced ammonia clearance and stimulation of muscle protein synthesis. l-carnitine also has multimodal effects on muscle and shows promise as a therapy for muscle loss through anti-inflammatory, antioxidant and ammonia lowering properties. Other nutraceuticals including l-ornithine l-aspartate, omega-3 polyunsaturated fatty acids and zinc and vitamin D supplementation, may similarly have positive effects on muscle homeostasis, however further evidence to support their use in cirrhotic populations is required., Conclusion: Nutraceuticals offer a promising and likely safe adjunct to standard care for sarcopenia in cirrhosis. While there is most evidence to support the use of BCAA and l-carnitine supplementation, further well-designed clinical trials are needed to elucidate their efficacy as a therapy for muscle loss in this population., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real-world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti-nuclear antibody-positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune-mediated conditions, is required., (© 2021 Royal Australasian College of Physicians.)

Competing Interests: Nil.

Background: There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD)., Aim: To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD., Methods: A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records., Results: There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 10 8 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08)., Conclusion: Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy., (© 2020 John Wiley & Sons Ltd.)

Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 ( https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/ ). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.

Common variable immune deficiency (CVID) is a primary immunodeficiency disorder that is associated with abnormal liver function tests, however advanced liver disease is uncommon. Hepatopulmonary syndrome (HPS) is a rare but debilitating complication of CVID-associated liver disease. We report a case of CVID complicated by HPS that was successfully treated with orthotopic liver transplant, with the patient recovering to normal hepatic function and successfully weaning off domiciliary oxygen post-transplantation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Limitations to the use of long-term Hepatitis B Immunoglobulin (HBIg) following liver transplantation for hepatitis B (HBV) have led to the substitution of HBIg with oral nucleo(s)tide analogue prophylaxis. We prospectively assessed the long-term safety and efficacy of switching to tenofovir disoproxil fumarate (TDF) from HBIg., Methods: An open-label, multicenter switch study was conducted to evaluate the substitution of TDF for HBIg whilst continuing lamivudine (LAM) therapy in preventing the recurrence of HBV in patients who had been maintained as hepatitis B surface antigen (HBsAg)-negative posttransplantation for at least 12 months., Results: Eighteen patients were enrolled (median age 66 years, range 42-78 years); 84% were male, and 78% on calcineurin inhibitors. Median time after transplantation was 14 years (range 5-19), and median duration of HBIg/LAM prior to the switch was 10 years (range 1-14). Median follow-up was 5 years (range 5-8). Of 18 patients, 16 (89%) remained HBsAg and HBV DNA negative at the end of follow-up. Two patients had re-emergence of HBsAg without a detectable HBV DNA and no clinical sequelae. Creatinine clearance significantly reduced (median 59 mL/min to 51 mL/min, P = 0.03), necessitating dose reduction of TDF in six (33%) participants, with two eventually ceasing TDF. One patient switched back to HBIg by choice. All patients who changed therapy maintained an undetectable HBsAg., Conclusion: Substitution of HBIg with TDF in patients on LAM is well tolerated and effective for the long-term prevention of HBV recurrence posttransplantation. Renal dysfunction occurs frequently in the posttransplant setting and can require dose adjustment of TDF or change of therapy.

We describe a case of bladder cancer presenting with atraumatic chylous ascites, which remains an extremely rare presentation of this condition. A previously well, elderly ex-smoker with no prior history of abdominal surgery was referred for investigation of progressive dyspnoea, increasing peripheral oedema and new-onset ascites, on a background of long-standing alcohol consumption (four standard drinks daily). Liver biochemistry and coagulation profile were normal apart from marked hypoalbuminaemia. Doppler ultrasound of the liver demonstrated normal echotexture and patent vasculature. Abdominal paracentesis yielded 8 L of milk-coloured, triglyceride-rich fluid with abundant malignant cells. Urine cytology demonstrated malignant transitional cells, with radiological evidence of a large enhancing bladder mass, with evidence of adjacent lymphadenopathy and omental involvement. A diagnosis of metastatic stage IV transitional cell bladder cancer was made. The patient declined palliative chemotherapy and passed away 2 months after their initial presentation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Molecular dynamics simulations is an important application in theoretical chemistry, and with the large high-performance computing resources available today the programs also generate huge amounts of output data. In particular in life sciences, with complex biomolecules such as proteins, simulation projects regularly deal with several terabytes of data. Apart from the need for more cost-efficient storage, it is increasingly important to be able to archive data, secure the integrity against disk or file transfer errors, to provide rapid access, and facilitate exchange of data through open interfaces. There is already a whole range of different formats used, but few if any of them (including our previous ones) fulfill all these goals. To address these shortcomings, we present "Trajectory Next Generation" (TNG)--a flexible but highly optimized and efficient file format designed with interoperability in mind. TNG both provides state-of-the-art multiframe compression as well as a container framework that will make it possible to extend it with new compression algorithms without modifications in programs using it. TNG will be the new file format in the next major release of the GROMACS package, but it has been implemented as a separate library and API with liberal licensing to enable wide adoption both in academic and commercial codes., (Copyright © 2013 Wiley Periodicals, Inc.)

Along with the growing evidence that relates membrane abnormalities to various diseases, biological membranes have been acknowledged as targets for therapy. Any such abnormality in the membrane structure alters the membrane potential which in principle can be captured by measuring properties of specific optical probes. There exists by now many molecular probes with absorption and fluorescence properties that are sensitive to local membrane structure and to the membrane potential. To suggest new high-performance optical probes for membrane-potential imaging it is important to understand in detail the membrane-induced structural changes in the probe, the membrane association dynamics of the probe, and its membrane-specific optical properties. To contribute to this effort, we here study an optical probe, N-acetylaladanamide (NAAA), in the presence of a POPC lipid bilayer using a multiscale integrated approach to assess the probe structure, dynamics, and optical properties in its membrane-bound status and in water solvent. We find that the probe eventually assimilates into the membrane with a specific orientation where the hydrophobic part of the probe is buried inside the lipid bilayer, while the hydrophilic part is exposed to the water solvent. The computed absorption maximum is red-shifted when compared to the gas phase. The computations of the two-photon absorption and second harmonic generation cross sections of the NAAA probe in its membrane-bound state which is of its first kind in the literature suggest that this probe can be used for imaging the membrane potential using nonlinear optical microscopy.

Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources., Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations., Availability: GROMACS is an open source and free software available from http://www.gromacs.org., Supplementary Information: Supplementary data are available at Bioinformatics online.

The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used pharmaceutically in cardiac treatment for centuries. The inhibitors block the pump by binding on its extracellular side and thereby locking it. To explore the possibilities for designing an alternative way of targeting the pump function, we have examined the structural requirements for binding to a pocket that accommodates the two C-terminal residues, YY, in the crystal structures of the pump. To cover the sample space of two residues, we first performed docking studies with the 400 possible dipeptides. For validation of the in silico predictions, pumps with 13 dipeptide sequences replacing the C-terminal YY were expressed in Xenopus laevis oocytes and examined with electrophysiology. Our data show a significant correlation between the docking scores from two different methods and the experimentally determined sodium affinities, which strengthens the previous hypothesis that sodium binding is coupled to docking of the C-terminus. From the dipeptides that dock the best and better than wild-type YY, it may therefore be possible to develop specific drugs targeting a previously unexplored binding pocket in the sodium pump.

Monoamine oxidase membrane enzymes are responsible for the catalytic breakdown of extra- and intracellular neurotransmitters and are targets for the development of central nervous system drugs. We analyzed the dynamics of rat MAOA by performing multiple independent molecular dynamics simulations of membrane-bound and membrane-free forms to clarify the relationship between the mechanics of the enzyme and its function, with particular emphasis on the significance of membrane attachment. Principal component analysis of the simulation trajectories as well as correlations in the fluctuations of the residues pointed to the existence of three domains that define the global dynamics of the protein. Interdomain anticorrelated movements in the membrane-bound system facilitated the relaxation of interactions between residues surrounding the substrate cavity and induced conformational changes which expanded the active site cavity and opened putative pathways for substrate uptake and product release. Such events were less pronounced in the membrane-free system due to differences in the nature of the dominant modes of motion. The presence of the lipid environment is suggested to assist in decoupling the interdomain motions, consistent with the observed reduction in enzyme activity under membrane-free conditions. Our results are also in accordance with mutational analysis which shows that modifications of interdomain hinge residues decrease the activity of rat MAOA in solution.

We describe the application of a special purpose board for molecular dynamics simulations, named MDGRAPE-3, to the problem of simulating periodic bio-molecular systems. MDGRAPE-3 is the latest board in a series of hardware accelerators designed to calculate the nonbonding long-range interactions much more rapidly than normal processors. So far, MDGRAPEs were mainly applied to isolated systems, where very many nonbonded interactions were calculated without any distance cutoff. However, in order to regulate the density and pressure during simulations of membrane embedded protein systems, one has to evaluate interactions under periodic boundary conditions. For this purpose, we implemented the Particle-Mesh Ewald (PME) method, and its approximation with distance cutoffs and charge neutrality as proposed by Wolf et al., using MDGRAPE-3. When the two methods were applied to simulations of two periodic biomolecular systems, a single MDGRAPE-3 achieved 30-40 times faster computation times than a single conventional processor did in the both cases. Both methods are shown to have the same molecular structures and dynamics of the systems., (Copyright 2008 Wiley Periodicals, Inc.)