Wang-Landau molecular dynamics technique to search for low-energy conformational space of proteins

Multicanonical molecular dynamics (MD) is a powerful technique for sampling conformations on rugged potential surfaces such as protein. However, it is notoriously difficult to estimate the multicanonical temperature effectively. Wang and Landau developed a convenient method for estimating the density of states based on a multicanonical Monte Carlo method. In their method, the density of states is calculated autonomously during a simulation. In this paper we develop a set of techniques to effectively apply the Wang-Landau method to MD simulations. In the multicanonical MD, the estimation of the derivative of the density of states is critical. In order to estimate it accurately, we devise two original improvements. First, the correction for the density of states is made smooth by using the Gaussian distribution obtained by a short canonical simulation. Second, an approximation is applied to the derivative, which is based on the Gaussian distribution and the multiple weighted histogram technique. A test of this method was performed with small polypeptides, Met-enkephalin and Trp-cage, and it is demonstrated that Wang-Landau MD is consistent with replica exchange MD but can sample much larger conformational space.Comment: 8 pages, 7 figures, accepted for publication in Physical Review

Wall conditions in ORMAK

From surface effects in controlled thermonuclear fusion devices and reactors meeting; Argonne, Illnois, USA (10 Jan 1974). ORMAK is a diffuse toroidal pinch with typical plasma currents of 100 kA, electron temperatures of 800 eV, and ion temperatures of 300 eV. The walls of the plasma region are made of stainless steel coated with an intermediate layer of platinum 0.05 mu thick and an outer 1 to 2 mu layer of gold. Tests with an Ion Microprobe Mass Analyzer have shown that the platinum acts to decrease diffusion of impurities from the stalnless steel to the surface. Gold was chosen to inhibit the surface chemical adsorption of gases. Studies with a movable limiter indicate that electron energy is lost at the plasma edge mainly via line radiation and cooling on ions, while ions are lost from the plasma by charge exchange. Thus the walls are bombarded by energetic neutrals, line radiation and, in addition, bremsstrahlung x-rays. The flux of energetic neutrals is measured by a charge exchange analyzer. Wall bombardment by such neutrals should cause sputtering, and gold has been observed spectroscopically near the limiter, increasing with time during a shot, However, analysis of impurities coated on a window by the discharge indicated very little gold sputtering and re-deposition. To measure the sputterirg rate, a wall sample was coated with 105 A of radioactive gold and bombarded with neutrals from ORMAK during a day's run. No measurable sputtering was found within the counting statistics of the measurement, but surface carbon contamination of the sample prevented any final conclusions. (auth

An effective all-atom potential for proteins

We describe and test an implicit solvent all-atom potential for simulations of protein folding and aggregation. The potential is developed through studies of structural and thermodynamic properties of 17 peptides with diverse secondary structure. Results obtained using the final form of the potential are presented for all these peptides. The same model, with unchanged parameters, is furthermore applied to a heterodimeric coiled-coil system, a mixed alpha/beta protein and a three-helix-bundle protein, with very good results. The computational efficiency of the potential makes it possible to investigate the free-energy landscape of these 49--67-residue systems with high statistical accuracy, using only modest computational resources by today's standards

Identification of five fundamental implicit theories underlying cognitive distortions in child abusers : a preliminary study

Qualitative analysis of interviews with 22 child abusers found strong evidence for Ward and Keenan\u27s (1999) proposal that there are five implicit theories in child abusers that account for the majority of their cognitive distortions/thinking errors. These implicit theories are: Child as a sexual being where children are perceived as being able to and wanting to engage in sexual activity with adults and also are not be harmed by such sexual contact; Nature of harm where the offender perceives that sexual activity does not cause harm (and may in fact be beneficial) to the child; Entitlement where the child abuser perceives that he is superior and more important than others: and hence is able to have sex with whoever, and whenever, he wants; Dangerous world where the offender perceives that that others are abusive and rejecting and he must fight to regain control; and Uncontrollable where the offender perceives the world as uncontrollable and hence he believes that circumstances are outside of his control. There was no evidence for any other type of implicit theory. Results of the study also indicated that there was a significant difference in terms of the endorsement of the Dangerous world implicit theory between participants reporting a history of child sexual abuse and those who did not. Offenders against male victims were significantly more likely to endorse the Child as a sexual being and Dangerous world implicit theories compared to men who had offended against female children

An enhanced partial order curve comparison algorithm and its application to analyzing protein folding trajectories

<p>Abstract</p> <p>Background</p> <p>Understanding how proteins fold is essential to our quest in discovering how life works at the molecular level. Current computation power enables researchers to produce a huge amount of folding simulation data. Hence there is a pressing need to be able to interpret and identify novel folding features from them.</p> <p>Results</p> <p>In this paper, we model each folding trajectory as a multi-dimensional curve. We then develop an effective multiple curve comparison (MCC) algorithm, called the <it>enhanced partial order (EPO) </it>algorithm, to extract features from a set of diverse folding trajectories, including both successful and unsuccessful simulation runs. The EPO algorithm addresses several new challenges presented by comparing high dimensional curves coming from folding trajectories. A detailed case study on miniprotein Trp-cage <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> demonstrates that our algorithm can detect similarities at rather low level, and extract biologically meaningful folding events.</p> <p>Conclusion</p> <p>The EPO algorithm is general and applicable to a wide range of applications. We demonstrate its generality and effectiveness by applying it to aligning multiple protein structures with low similarities. For user's convenience, we provide a web server for the algorithm at <url>http://db.cse.ohio-state.edu/EPO</url>.</p

A Natural Love of Natural Products

Recent research on the chemistry of natural products from the author’s group that led to the receipt of the ACS Ernest Guenther Award in the Chemistry of Natural Products is reviewed. REDOR NMR and synthetic studies established the T-taxol conformation as the bioactive tubulin-binding conformation, and these results were confirmed by the synthesis of compounds which clearly owed their activity or lack of activity to whether or not they could adopt the T-taxol conformation. Similar studies with the epothilones suggest that the current tubulin-binding model needs to be modified. Examples of natural products discovery and biodiversity conservation in Suriname and Madagascar are also presented, and it is concluded that natural products chemistry will continue to make significant contributions to drug discovery. My first real exposure to natural products chemistry came in my third and final year as an undergraduate at Cambridge University, when I attended a course of lectures on the chemistry of natural products by the Nobel Prize-winning chemist Sir Alexander Todd (later to become Lord Todd). The lectures included many references to his own work in the field, with stories of his early work on the structure of cholesterol, th

On the Zwitterionic Nature of Gas-Phase Peptides and Protein Ions

Determining the total number of charged residues corresponding to a given value of net charge for peptides and proteins in gas phase is crucial for the interpretation of mass-spectrometry data, yet it is far from being understood. Here we show that a novel computational protocol based on force field and massive density functional calculations is able to reproduce the experimental facets of well investigated systems, such as angiotensin II, bradykinin, and tryptophan-cage. The protocol takes into account all of the possible protomers compatible with a given charge state. Our calculations predict that the low charge states are zwitterions, because the stabilization due to intramolecular hydrogen bonding and salt-bridges can compensate for the thermodynamic penalty deriving from deprotonation of acid residues. In contrast, high charge states may or may not be zwitterions because internal solvation might not compensate for the energy cost of charge separation