Locating binding poses in protein-ligand systems using reconnaissance metadynamics

A molecular dynamics-based protocol is proposed for finding and scoring protein-ligand binding poses. This protocol uses the recently developed reconnaissance metadynamics method, which employs a self-learning algorithm to construct a bias that pushes the system away from the kinetic traps where it would otherwise remain. The exploration of phase space with this algorithm is shown to be roughly six to eight times faster than unbiased molecular dynamics and is only limited by the time taken to diffuse about the surface of the protein. We apply this method to the well-studied trypsin-benzamidine system and show that we are able to refind all the poses obtained from a reference EADock blind docking calculation. These poses can be scored based on the length of time the system remains trapped in the pose. Alternatively, one can perform dimensionality reduction on the output trajectory and obtain a map of phase space that can be used in more expensive free-energy calculations.

Exploring the free energy surfaces of clusters using reconnaissance metadynamics

A new approach is proposed for exploring the low-energy structures of small to medium-sized aggregates of atoms and molecules. This approach uses the recently proposed reconnaissance metadynamics method [G. A. Tribello, M. Ceriotti, and M. Parrinello. Proc. Natl. Acad. Sci. U.S.A. 107(41), 17509 (2010)] in tandem with collective variables that describe the average structure of the coordination sphere around the atoms/molecules. We demonstrate this method on both Lennard-Jones and water clusters and show how it is able to quickly find the global minimum in the potential energy surface, while exploring the finite temperature free energy surface. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3628676]

Simplifying the representation of complex free-energy landscapes using sketch-map

A new scheme, sketch-map, for obtaining a low-dimensional representation of the region of phase space explored during an enhanced dynamics simulation is proposed. We show evidence, from an examination of the distribution of pairwise distances between frames, that some features of the free-energy surface are inherently high-dimensional. This makes dimensionality reduction problematic because the data does not satisfy the assumptions made in conventional manifold learning algorithms We therefore propose that when dimensionality reduction is performed on trajectory data one should think of the resultant embedding as a quickly sketched set of directions rather than a road map. In other words, the embedding tells one about the connectivity between states but does not provide the vectors that correspond to the slow degrees of freedom. This realization informs the development of sketch-map, which endeavors to reproduce the proximity information from the high-dimensionality description in a space of lower dimensionality even when a faithful embedding is not possible.

A self-learning algorithm for biased molecular dynamics

A new self-learning algorithm for accelerated dynamics, reconnaissance metadynamics, is proposed that is able to work with a very large number of collective coordinates. Acceleration of the dynamics is achieved by constructing a bias potential in terms of a patchwork of one-dimensional, locally valid collective coordinates. These collective coordinates are obtained from trajectory analyses so that they adapt to any new features encountered during the simulation. We show how this methodology can be used to enhance sampling in real chemical systems citing examples both from the physics of clusters and from the biological sciences.

Asprich Peptides Are Occluded in Calcite and Permanently Disorder Biomineral Crystals

Macromolecules are a minority but important component of the minerals formed by living organisms, or biominerals. The role these macromolecules play at the early stages of biomineral formation, as well as their long-term and long-range effects on the mature biomineral, is poorly understood. A 42-amino acid peptide, asp2, was derived from the Asprich family of proteins. In this study we present X-ray absorption near-edge structure spectroscopy and X-ray photoelectron emission microscopy data from the asp2 peptide, the calcite (CaCO3) crystals, and the peptide + crystal composites. The results clearly show that asp2 is occluded in fully formed biomineral crystals and slightly but permanently disorders the crystal structure at short- and long-range distances.

A Molecular Dynamics Study of the Early Stages of Calcium Carbonate Growth

The precipitation of calcium carbonate in water has been examined using a combination of molecular dynamics and umbrella sampling. During 20 ns molecular dynamics trajectories at elevated calcium carbonate concentrations, amorphous particles are observed to form and appear to be composed of misaligned domains of vaterite and aragonite. The addition of further calcium ions to these clusters is found to be energetically favorable and virtually barrierless. By contrast, there is a large barrier to the addition of calcium to small calcite crystals. Thus, even though calcite nanocrystals are stable in solution, at high supersaturations, particles of amorphous material form because this material grows much faster than ordered calcite nanocrystals.

Binding of Calcium and Carbonate to Polyacrylates

Polyacrylate molecules can be used to slow the growth of calcium carbonate. However, little is known about the mechanism by which the molecules impede the growth rate. A recent computational study (Bulo et al. Macromolecules 2007, 40, 3437) used metadynamics to investigate the binding of calcium to polyacrylate chains and has thrown some light on the coiling and precipitation of these polymers. We extend these simulations to examine the binding of calcium and carbonate to polyacrylate chains. We show that calcium complexed with both carbonate and polyacrylate is a very stable species. The free energies of calcium-carbonate-polyacrylate complexes, with different polymer configurations, are calculated, and differences in the free energy of the binding of carbonate are shown to be due to differences in the amount of steric hindrance about the calcium, which prevents the approach of the carbonate ion.

The trauma still goes on...: The multigenerational legacy of Northern Ireland's conflict

Numerous studies have been conducted internationally on the subject of multigenerational trauma; however, little is currently known about its existence in the context of the Northern Ireland conflict. The present study explored the outcomes of and mechanisms through which the trauma of one generation impacts on subsequent generations in this context. Using an Interpretative Phenomenological Approach (IPA), this study examined the subjective experiences, beliefs and perceptions of four mothers from Northern Ireland, all of whom had endured trauma during their childhoods. Three main master themes emerged: 1. "Attempting to cope" addressed how the trauma was dealt with, and how these efforts can be the very mechanisms through which multigenerational trauma occurs. Examples include hiding the truth, seeing the truth as dangerous, and knowing and not knowing about the trauma; 2. "The trauma still goes on" highlighted the negative outcomes and consequences of the traumatic experiences within the family such as delayed impact, symptoms and anger; and 3. "Strength through adversity" included the more positive outcomes of their experiences, such as finding meaning through suffering and making efforts to stop the cycle. The results are discussed in terms of the existing theories on multigenerational trauma, and implications for practice are explored.

Combining diverse knowledge: The role of specialist and generalist learning

Purpose
– The aim of this paper is to contribute to understanding the nature of specialist and generalist human capital by exploring the ways in which knowledge workers view their experience of working in specialist and generalist roles in pharmaceutical firms in Ireland and the UK.

Design/methodology/approach
– The findings are based on interviews with 55 knowledge workers employed in a range of scientific, technical and managerial positions in four Irish and two UK firms located in the pharmaceutical sector. Interviews were also conducted with nine human resource/training and development managers within these six firms.

Findings
– The findings suggest that the categorisation of human capital as either specialist or generalist is too rigid and does not take account of the fact that individuals may themselves choose to shape their careers by investing in a range of education, training and development opportunities that will enable them to move between specialist and generalist roles.

Originality/value
– The paper unpacks the concepts of specialist and generalist human capital from an employee perspective and challenges the sharp distinction that is made between specialist and generalist human capital.

The state and industrial policy in Ireland: a case study of the Irish pharmaceutical sector

There is renewed interest in the state's role in the economic sphere but a lack of research on the viability and employment effects of alternative economic models, in particular from a ‘liberal market economy’ perspective. This article addresses this gap in the human resource management literature by undertaking a detailed case study of industrial policy in the Irish pharmaceutical sector. The proactive and resource-intensive industrial policy adopted by the Irish government and development agencies is found to have underpinned a significant strategic upgrading in this sector of the Irish economy. In turn this has facilitated the growth of high-wage, high-skill jobs. The findings highlight the potential for an active industrial policy to promote employment upgrading in liberal market economies.

Common variant at 16p11.2 conferring risk of psychosis

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).

CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analysed 6,882 cases and 11,255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in an additional 14,568 cases and 15,274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P500kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.