Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

BATS OF THE WEST INDIAN ISLAND OF DOMINICA: NATURAL HISTORY, AREOGRAPHY, AND TROPHIC STRUCTURE

Because the islands in the Caribbean long have interested students of mammals and zoogeography, considerable information has been published concerning the biology of the Antillean mammalian fauna in the past three decades (Jones and Schwartz, 1967; Schwartz and Jones, 1967; Koopman, 1968, 1989; Jones and Phillips, 1970, 1976; Varona, 1974; Baker and Genoways, 1978; Baker et al., 1978; Swanepoel and Genoways, 1978; Jones and Baker, 1979; Silva Taboada, 1979; Baker et al., 1984; Eshelman and Morgan, 1985; Buden, 1986; Griffiths and Klingener, 1988; Jones, 1989; Masson et al., 1990; Pederson et al., 1996; Genoways et al., 1998). This increasing interest in the systematics and zoogeography of mammals in the region has involved both studies in the field and re-examination of collections made in earlier years. One problem facing investigators who attempt to assess the faunal relationships of the Antilles is the fact that natural conditions on most islands have been altered significantly as a result of early settlement, first by Ameridians, then by Europeans beginning in the 1500s. Changes wrought by agricultural practices have destroyed much of the original environment, and introduction on many islands of the mongoose (Herpestes javanicus) as a supposed means of controlling introduced rats (both Rattus norvegicus and R. rattus) has disturbed natural conditions

Business game as instrument of staff recruitment

The aim of the article consists in giving the reader some information on recruiting and business game as the instrument of staff recruitment. The article explains the concept of the business game and its role in the recruitment of staff, also the basic rules and forms of the business game.Цель статьи состоит в предоставлении читателю информации о рекрутинге и деловой игре как инструменте подбора персонала. Статья объясняет понятие деловой игры и ее роли в наборе персонала, а также основные правила и формы деловой игры

Учет оплаты труда на примере ООО «Клининговая компания Моррис»

В работе рассмотрены теоретические аспекты начисления заработной платы, начисления и удержания. Приведена практическая реализация на примере ООО. Выявлены ошибки и предложены рекомендации предприятию.The paper considers the theoretical aspects of payroll, accrual and retention. The practical implementation of the example of LLC. Errors were identified and recommendations made to the enterprise

RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation.Fil: Wu, Yonghe. Max Planck Institute of Psychiatry; AlemaniaFil: Tedesco, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Kristin, Lucia. Max Planck Institute of Psychiatry; AlemaniaFil: Schlitter, Anna M.. Universitat Technical Zu Munich; AlemaniaFil: Monteserin Garcia, Jose. Max Planck Institute of Psychiatry; AlemaniaFil: Esposito, Irene. Universitat Technical Zu Munich; AlemaniaFil: Auernhammer, Christoph J.. Universitat Technical Zu Munich; AlemaniaFil: Theodoropoulou, Marily. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Renner, Ulrich. Max Planck Institute of Psychiatry; AlemaniaFil: Stalla, Günter K.. Max Planck Institute of Psychiatry; Alemani

Maximum Flux Transition Paths of Conformational Change

Given two metastable states A and B of a biomolecular system, the problem is to calculate the likely paths of the transition from A to B. Such a calculation is more informative and more manageable if done for a reduced set of collective variables chosen so that paths cluster in collective variable space. The computational task becomes that of computing the "center" of such a cluster. A good way to define the center employs the concept of a committor, whose value at a point in collective variable space is the probability that a trajectory at that point will reach B before A. The committor "foliates" the transition region into a set of isocommittors. The maximum flux transition path is defined as a path that crosses each isocommittor at a point which (locally) has the highest crossing rate of distinct reactive trajectories. (This path is different from that of the MaxFlux method of Huo and Straub.) It is argued that such a path is nearer to an ideal path than others that have been proposed with the possible exception of the finite-temperature string method path. To make the calculation tractable, three approximations are introduced, yielding a path that is the solution of a nonsingular two-point boundary-value problem. For such a problem, one can construct a simple and robust algorithm. One such algorithm and its performance is discussed.Comment: 7 figure

A New Species of Giant Sengi or Elephant-Shrew (Genus \u3cem\u3eRhynchocyon\u3c/em\u3e) Highlights the Exceptional Biodiversity of the Udzungwa Mountains of Tanzania

A new species of sengi, or elephant-shrew, is described. It was discovered in the northern Udzungwa Mountains of Tanzania in 2005. Sengis (Order Macroscelidea, super-cohort Afrotheria) include four genera and 15 species of mammals that are endemic to Africa. This discovery is a significant contribution to the systematics of this small order. Based on 49 camera trap images, 40 sightings and five voucher specimens, the new sengi is diurnal and distinguished from the other three species of Rhynchocyon by a grizzled grey face, pale yellow to cream chest and chin, orange-rufous sides, maroon back and jet-black lower rump and thighs. The body weight of the new species is about 700 g, which is 25–50% greater than any other giant sengi. The new Rhynchocyon is only known from two populations that cover about 300 km2 of montane forest. It has an estimated density of 50–80 individuals km−2. This discovery has important implications for the conservation of the high biodiversity that is found in the forests of the Eastern Arc Mountains

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society

Absolute Single-Molecule Entropies from Quasi-Harmonic Analysis of Microsecond Molecular Dynamics: Correction Terms and Convergence Properties

The convergence properties of the absolute single-molecule configurational entropy and the correction terms used to estimate it are investigated using microsecond molecular dynamics simulation of a peptide test system and an improved methodology. The results are compared with previous applications for systems of diverse chemical nature. It is shown that (i) the effect of anharmonicity is small, (ii) the effect of pairwise correlation is typically large, and (iii) the latter affects to a larger extent the entropy estimate of thermodynamic states characterized by a higher motional correlation. The causes of such deviations from a quasi-harmonic behavior are explained. This improved approach provides entropies also for molecular systems undergoing conformational transitions and characterized by highly frustrated energy surfaces, thus not limited to systems sampling a single quasi-harmonic basin. Overall, this study emphasizes the need for extensive phase-space sampling in order to obtain a reliable estimation of entropic contributions

Entropy of Molecular Binding at Solvated Mineral Surfaces

We present thermodynamic integration simulations for the binding of mannose and methanoic acid onto the {10.4} calcite surface producing free energy of binding values of −2.89 and −1.64 kJ mol–1, respectively. We extract the entropy of binding from vacuum-based simulations and use these values to determine the entropy of binding for surface water molecules which is ∼6 J mol–1 K–1