Molecular dynamics simulations and drug discovery

This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role

Generation of Covalently Closed Circular DNA of Hepatitis B Viruses via Intracellular Recycling Is Regulated in a Virus Specific Manner

Persistence of hepatitis B virus (HBV) infection requires covalently closed circular (ccc)DNA formation and amplification, which can occur via intracellular recycling of the viral polymerase-linked relaxed circular (rc) DNA genomes present in virions. Here we reveal a fundamental difference between HBV and the related duck hepatitis B virus (DHBV) in the recycling mechanism. Direct comparison of HBV and DHBV cccDNA amplification in cross-species transfection experiments showed that, in the same human cell background, DHBV but not HBV rcDNA converts efficiently into cccDNA. By characterizing the distinct forms of HBV and DHBV rcDNA accumulating in the cells we find that nuclear import, complete versus partial release from the capsid and complete versus partial removal of the covalently bound polymerase contribute to limiting HBV cccDNA formation; particularly, we identify genome region-selectively opened nuclear capsids as a putative novel HBV uncoating intermediate. However, the presence in the nucleus of around 40% of completely uncoated rcDNA that lacks most if not all of the covalently bound protein strongly suggests a major block further downstream that operates in the HBV but not DHBV recycling pathway. In summary, our results uncover an unexpected contribution of the virus to cccDNA formation that might help to better understand the persistence of HBV infection. Moreover, efficient DHBV cccDNA formation in human hepatoma cells should greatly facilitate experimental identification, and possibly inhibition, of the human cell factors involved in the process

Computational Lipidology: Predicting Lipoprotein Density Profiles in Human Blood Plasma

Monitoring cholesterol levels is strongly recommended to identify patients at risk for myocardial infarction. However, clinical markers beyond “bad” and “good” cholesterol are needed to precisely predict individual lipid disorders. Our work contributes to this aim by bringing together experiment and theory. We developed a novel computer-based model of the human plasma lipoprotein metabolism in order to simulate the blood lipid levels in high resolution. Instead of focusing on a few conventionally used predefined lipoprotein density classes (LDL, HDL), we consider the entire protein and lipid composition spectrum of individual lipoprotein complexes. Subsequently, their distribution over density (which equals the lipoprotein profile) is calculated. As our main results, we (i) successfully reproduced clinically measured lipoprotein profiles of healthy subjects; (ii) assigned lipoproteins to narrow density classes, named high-resolution density sub-fractions (hrDS), revealing heterogeneous lipoprotein distributions within the major lipoprotein classes; and (iii) present model-based predictions of changes in the lipoprotein distribution elicited by disorders in underlying molecular processes. In its present state, the model offers a platform for many future applications aimed at understanding the reasons for inter-individual variability, identifying new sub-fractions of potential clinical relevance and a patient-oriented diagnosis of the potential molecular causes for individual dyslipidemia

Evaluating Patterns of a White-Band Disease (WBD) Outbreak in Acropora palmata Using Spatial Analysis: A Comparison of Transect and Colony Clustering

. Likewise, there is little known about the spatiality of outbreaks. We examined the spatial patterns of WBD during a 2004 outbreak at Buck Island Reef National Monument in the US Virgin Islands. colonies with and without WBD.As the search for causation continues, surveillance and proper documentation of the spatial patterns may inform etiology, and at the same time assist reef managers in allocating resources to tracking the disease. Our results indicate that the spatial scale of data collected can drastically affect the calculation of prevalence and spatial distribution of WBD outbreaks. Specifically, we illustrate that higher resolution sampling resulted in more realistic disease estimates. This should assist in selecting appropriate sampling designs for future outbreak investigations. The spatial techniques used here can be used to facilitate other coral disease studies, as well as, improve reef conservation and management

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine

Basic Science Considerations in Primary Total Hip Replacement Arthroplasty

Total Hip Replacement is one of the most common operations performed in the developed world today. An increasingly ageing population means that the numbers of people undergoing this operation is set to rise. There are a numerous number of prosthesis on the market and it is often difficult to choose between them. It is therefore necessary to have a good understanding of the basic scientific principles in Total Hip Replacement and the evidence base underpinning them. This paper reviews the relevant anatomical and biomechanical principles in THA. It goes on to elaborate on the structural properties of materials used in modern implants and looks at the evidence base for different types of fixation including cemented and uncemented components. Modern bearing surfaces are discussed in addition to the scientific basis of various surface engineering modifications in THA prostheses. The basic science considerations in component alignment and abductor tension are also discussed. A brief discussion on modular and custom designs of THR is also included. This article reviews basic science concepts and the rationale underpinning the use of the femoral and acetabular component in total hip replacement

Vitamin C and the common cold: a retrospective analysis of Chalmers’ review.

In 1975 Thomas Chalmers analyzed the possible effect of vitamin C on the common cold by calculating the average difference in the duration of cold episodes in vitamin C and control groups in seven placebo-controlled studies. He found that episodes were 0.11 +/- 0.24 (SE) days shorter in the vitamin C groups and concluded that there was no valid evidence to indicate that vitamin C is beneficial in the treatment of the common cold. Chalmers' review has been extensively cited in scientific articles and monographs. However, other reviewers have concluded that vitamin C significantly alleviates the symptoms of the common cold. A careful analysis of Chalmers' review reveals serious shortcomings. For example, Chalmers did not consider the amount of vitamin C used in the studies and included in his meta-analysis was a study in which only 0.025-0.05 g/day of vitamin C was administered to the test subjects. For some studies Chalmers used values that are inconsistent with the original published results. Using data from the same studies, we calculated that vitamin C (1-6 g/day) decreased the duration of the cold episodes by 0.93 +/- 0.22 (SE) days; the relative decrease in the episode duration was 21%. The current notion that vitamin C has no effect on the common cold seems to be based in large part on a faulty review written two decades ago

A new measure of longitudinal connectivity for stream networks

Habitat connectivity is a central factor in shaping aquatic biological communities, but few tools exist to describe and quantify this attribute at a network scale in riverine systems. Here, we develop a new index to quantify longitudinal connectivity of river networks based on the expected probability of an organism being able to move freely between two random points of the network. We apply this index to two fish life histories and evaluate the effects of the number, passability, and placement of barriers on river network connectivity through the use of simulated dendritic ecological networks. We then extend the index to a real world dendritic river system in Newfoundland, Canada. Our results indicate that connectivity in river systems, as represented by our index, is most impacted by the first few barriers added to the system. This is in contrast to terrestrial systems, which are more resilient to low levels of connectivity. The results show a curvilinear relationship between barrier passability and structural connectivity. This suggests that an incremental improvement in passability would result in a greater improvement to river network connectivity for more permeable barriers than for less permeable barriers. Our analysis of the index in simulated and real river networks also showed that barrier placement played an important role in connectivity. Not surprisingly, barriers located near the river mouth have the greatest impact on fish with diadromous life histories while those located near the center of the river network have the most impact on fish with potadromous life histories. The proposed index is conceptually simple and sufficiently flexible to deal with variations in river structure and biological communities. The index will enable researchers to account for connectivity in habitat studies and will also allow resource managers to characterize watersheds, assess cumulative impacts of multiple barriers and determine priorities for restoration