CHARMM: The biomolecular simulation program Brooks, B.R; Brooks, C.L. III; Mackerell, A.D. Jr ...
Journal of computational chemistry,
30 July 2009, Letnik:
30, Številka:
10
Journal Article
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CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on ...molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.
We investigated the origins and interrelations of causal knowledge and knowledge of agency in 3-month-old infants, who cannot yet effect changes in the world by reaching for, grasping, and picking up ...objects. Across 5 experiments, n = 152 prereaching infants viewed object-directed reaches that varied in efficiency (following the shortest physically possible path vs. a longer path), goal (lifting an object vs. causing a change in its state), and causal structure (action on contact vs. action at a distance and after a delay). Prereaching infants showed no strong looking preference between a person’s efficient and inefficient reaches when the person grasped and displaced an object. When the person reached for and caused a change in the state of the object on contact, however, infants looked longer when this action was inefficient than when it was efficient. Three-month-old infants also showed a key signature of adults’ and older infants’ causal inferences: This looking preference was abolished if a short spatial and temporal gap separated the action from its effect. The basic intuition that people are causal agents, who navigate around physical constraints to change the state of the world, may be one important foundation for infants’ ability to plan their own actions and learn from the acts of others.
Living systems have evolved remarkable molecular functions that can be redesigned for in vivo chemical synthesis as we gain a deeper understanding of the underlying biochemical principles for de novo ...construction of synthetic pathways. We have focused on developing pathways for next-generation biofuels as they require carbon to be channeled to product at quantitative yields. However, these fatty acid-inspired pathways must manage the highly reversible nature of the enzyme components. For targets in the biodiesel range, the equilibrium can be driven to completion by physical sequestration of an insoluble product, which is a mechanism unavailable to soluble gasoline-sized products. In this work, we report the construction of a chimeric pathway assembled from three different organisms for the high-level production of n-butanol (4,650 ± 720 mg l⁻¹) that uses an enzymatic chemical reaction mechanism in place of a physical step as a kinetic control element to achieve high yields from glucose (28%).
Industrial suspension polymerization usually proceeds by a free‐radical mechanism to produce polymer beads. The size distribution of the polymer beads is often similar to that of the polymerizing ...drops in the reactor. That distribution is determined by the operating mechanisms of drop breakage and drop coalescence. Consequently, the value of the Reynolds number is significant and a potential change in flow regime must be considered in reactor scale‐up. The choice of suspending agent, which can be a water‐miscible polymer or a finely divided particulate solid, can affect both the drop size and the properties of the final product. High monomer conversions are attainable but reaction kinetics can be affected by increases in drop viscosity during the polymerization. Drop mixing, which sometimes takes place, can be slow, so that non‐uniformity occurs in the final product. With copolymerization, complications can arise if the initiator, or one of the monomers, is partially soluble in the continuous phase. Adverse environmental impact of suspension polymerization can be avoided by cleaning and/or recycling the continuous phase when it leaves the reactor.
In suspension polymerization, control of drop size distribution requires clear determination of the reactor flow regime and an appropriate choice of suspending agent. Partial miscibility of some reaction components with the continuous phase and slow drop mixing can both affect the final polymer properties.
Chronic exposure to arsenic causes adverse health effects in children. Aberrant epigenetic modifications including altered DNA methylation pattern are one of the major steps towards malignant ...transformation of cells. Our group has previously identified significant alteration in DNA methylation mark in arsenic exposed adults, affecting major biological pathways. Till date, no information is available exploring the altered DNA methylation mark in telomere regulation and altered mitochondrial functionality in association with DNA damage in arsenic-exposed children. Our study aims in identifying signature epigenetic pattern associated with telomere lengthening, mitochondrial functionality and DNA damage repair in children with special emphasis on DNA methylation. Biological samples (blood and urine) and drinking water were collected from the children aged between 5 and 16 years of arsenic exposed areas (N = 52) of Murshidabad district and unexposed areas (N = 50) of East Midnapur districts, West Bengal, India. Methylation-specific PCR was performed to analyse subtelomeric methylation status and promoter methylation status of target genes. Results revealed altered DNA methylation profile in the exposed children compared to unexposed. Promoter hypermethylation was observed in MLH1 and MSH2 (p < 0.05 and p < 0.001) indicating inefficiency in DNA damage repair. Hypomethylation in mitochondrial D-loop (p < 0.05) and TFAM promoter region (p < 0.05) along with increased mitochondrial DNA copy number among exposed children was also observed. Significant increase in telomere length and region specific subtelomeric hypermethylation (XpYp, p < 0.05) was found. Analysis of S-Adenosyl Methionine (SAM) and 8-oxoDG level revealed significant depletion of SAM (p < 0.001) and elevated oxidative DNA damage (p < 0.001) respectively in arsenic toxicity. Our study identified key methylation patterns in arsenic-exposed children which may act as an early predictive biomarker in the near future. Further in-depth studies involving large sample size and transcriptomic analysis are required for understanding the mechanistic details.
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•Altered DNA methylation pattern was observed in arsenic-exposed children.•Depletion of SAM pool in exposed children as a result of aberrant DNA methylation•Higher MtDNA copy no. and 8-oxoDG levels were found in children exposed to arsenic.•Comparison between exposed adults and children revealed similar epigenetic patterns.
Three months of Doppler lidar wind measurements were obtained during the Arctic Cloud Summer Experiment on the icebreaker Oden during the summer of 2014. Such ship-borne Doppler measurements require ...active stabilisation to remove the effects of ship motion. We demonstrate that the combination of a commercial Doppler lidar with a custom-made motion-stabilisation platform enables the retrieval of wind profiles in the Arctic atmospheric boundary layer during both cruising and ice-breaking with statistical uncertainties comparable to land-based measurements. This held true particularly within the atmospheric boundary layer even though the overall aerosol load was very low. Motion stabilisation was successful for high wind speeds in open water and the resulting wave conditions. It allows for the retrieval of vertical winds with a random error below 0.2 m s−1. The comparison of lidar-measured wind and radio soundings gives a mean bias of 0.3 m s−1 (2°) and a mean standard deviation of 1.1 m s−1 (12°) for wind speed (wind direction). The agreement for wind direction degrades with height. The combination of a motion-stabilised platform with a low-maintenance autonomous Doppler lidar has the potential to enable continuous long-term high-resolution ship-based wind profile measurements over the oceans.
Though antibiotic resistance (ABR) represents a major global health threat, contributions of landfill leachate to the life cycle of antibiotics and ABR development are poorly understood in rapidly ...urbanizing regions of developing countries. We selected one of the largest active landfills in Asia and two landfills that have been closed for 20 years to examine antibiotic occurrences in leachates and associated hazards during wet and dry season sampling events. We focused on some of the most commonly used human antibiotics in Hong Kong, one of the most populous Asian cities and the fourth most densely populated cities in the world. Seven antibiotics (cephalexin CLX, chloramphenicol CAP, ciprofloxacin CIP, erythromycin ERY, roxithromycin ROX, trimethoprim TMP, sulfamethoxazole SMX) were quantitated using HPLC-MS/MS generally following previously reported methods. Whereas CLX, CAP, ROX and SMX in leachates did not exceed ABR predicted no effect concentrations (PNECs), exceedances were observed for CIP, ERY and TMP in some study locations and on some dates. In fact, an ABR PNEC for CIP was exceeded in leachates during both sampling periods from all study locations, including leachates that are directly discharged to coastal systems. These findings highlight the importance of developing an advanced understanding of pharmaceutical access, usage and disposal practices, effectiveness of intervention strategies (e.g., leachate treatment technologies, drug take-back schemes), and contributions of landfill leachates to the life cycle of antibiotics and ABR development, particularly in rapidly urbanizing coastal regions with less advanced waste management systems than Hong Kong.
•CIP & ERY levels in raw leachate from landfill closed for 20 years are very high.•The PNECs for resistance selection of CIP, ERY & TMP have been exceeded.•This poses threats to the development of antibiotic resistance in HK waters.•Policy intervention in the form of a drug take-back scheme is warranted.
Observational tuberculosis cohort studies are often limited by a lack of long-term data characterizing survival beyond the initial treatment outcome. Though Cox proportional hazards models are often ...applied to these data, differential risk of long-term survival, dependent on the initial treatment outcome, can lead to violations of model assumptions. We evaluate the performance of two alternate censoring approaches on reducing bias in treatment effect estimates.
We simulate a typical multidrug-resistant tuberculosis cohort study and use Cox proportional hazards models to assess the relationship of an aggressive treatment regimen with hazard of death. We compare three assumptions regarding censored observations to determine which produces least biased treatment effect estimates: conventional non-informative censoring, an extension of short-term survival informed by literature, and incorporation of predicted long-term vital status.
The treatment regimen's protective effect on death is consistently underestimated by the conventional censoring method, up to 7.6%. Models using the two alternative censoring techniques produce treatment effect estimates consistently stronger and less biased than the conventional method, underestimating the treatment effect by less than 2.4% across all scenarios.
When model assumptions are violated, alternative censoring techniques can more accurately estimate associations between treatment and long-term survival. In multidrug-resistant tuberculosis cohort analyses, this bias reduction may yield more accurate and, larger effect estimates. This bias reduction can be achieved through use of standard statistical procedures with a simple re-coding of the censoring indicator.
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