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Search Results: 1 - 10 of 1369 matches for " Don McCammon "
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Medical Food to Stop the Progression of Parkinson’s Disease  [PDF]
Don McCammon
Advances in Parkinson's Disease (APD) , 2014, DOI: 10.4236/apd.2014.32003
Abstract:

No progress has been made in the development of drugs to stop the progression of Parkinson’s Disease. Here the author has presented a novel approach to stopping the disease using a dietary supplement primarily composed of Mannitol. In vivo animal studies have shown that Mannitol was able to break up alpha-synuclein clusters and restore functioning in transgenic drosophila and mice. The author, who has Parkinson’s, used himself as a subject and was able to achieve similar results.

The Association of Tetrameric Acetylcholinesterase with ColQ Tail: A Block Normal Mode Analysis.
Zhang,McCammon
PLOS Computational Biology , 2005,
Abstract: Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT](4)PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChE(T)](4)-ColQ atomic structure model, based on the crystal structure of the [WAT](4)PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT](4)PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.
Semiconductor Thermistors
Dan McCammon
Physics , 2005, DOI: 10.1007/10933596_2
Abstract: Semiconductor thermistors operating in the variable range hopping conduction regime have been used in thermal detectors of all kinds for more than fifty years. Their use in sensitive bolometers for infrared astronomy was a highly developed empirical art even before the basic physics of the conduction mechanism was understood. Today we are gradually obtaining a better understanding of these devices, and with improvements in fabrication technologies thermometers can now be designed and built with predictable characteristics. There are still surprises, however, and it is clear that the theory of their operation is not yet complete. In this chapter we give an overview of the basic operation of doped semiconductor thermometers, outline performance considerations, give references for empirical design and performance data, and discuss fabrication issues.
Thermal Equilibrium Calorimeters -- An Introduction
Dan McCammon
Physics , 2005, DOI: 10.1007/10933596_1
Abstract: Near-equilibrium thermal detectors operate as classical calorimeters, with energy deposition and internal equilibration times short compared to the thermal time constant of the device. Advances in fabrication techniques, cryogenics, and electronics have made it practical to measure deposited energy with unprecedented sensitivity and precision. In this chapter we discuss performance considerations for these devices, including optimal filtering and energy resolution calculations. We begin with the basic theory of simple equilibrium calorimeters with ideal resistive thermometers. This provides a starting point for a brief discussion of electrothermal feedback, other noise sources, various non-ideal effects, and nonlinearity. We then describe other types of thermometers and show how they fit into this theoretical framework and why they may require different optimizations and figures of merit. Most of this discussion is applicable also to power detectors, or bolometers, where the detector time constants may be short compared to variations in the incident signal power.
Gated Diffusion-controlled Reactions
J Andrew McCammon
BMC Biophysics , 2011, DOI: 10.1186/2046-1682-4-4
Abstract: In science, it is recognized that solving one puzzle often reveals new puzzles. The determination of the first three-dimensional structure of a protein provided a famous example [1]. The protein involved was myoglobin, whose functions include the binding of oxygen molecules for storage and release as needed in muscle tissues. Inspection of a space-filling model of myoglobin immediately made clear that myoglobin could not function if the protein were rigid, since the polypeptide chain folded into a solid wall around the buried heme group to which the oxygen molecule binds; the same conundrum was soon found for hemoglobin. The puzzle of how ligands bind was discussed in a classic paper by Perutz and Mathews, in which they noted that there must be thermally excited fluctuations in the protein structures that enable ligand molecules to migrate between the external solvent and the heme binding groups [2].Subsequent studies of protein structure and function have shown that structural fluctuations are, in fact, often required for ligand binding and release [3]. An early analysis of the kinetic consequences of such "gated" binding processes was presented by McCammon and Northrup in 1981 [4]. This revealed two limiting cases, for a binding site that is highly reactive when exposed. In the fast gating limit, for which opening and closing of the gate is much faster than the rate of escape of ligand from the neighborhood of the gate into the surrounding solvent, the rate of binding approaches that of the always-open protein. In the slow gating limit, for which opening and closing of the gate is much slower than the rate of escape of the ligand, the rate approaches that of the always-open protein multiplied by the fraction of the time the gate is open.The years since 1981 have seen marked improvements in the theoretical underpinnings for the analyses of gated diffusion-controlled reactions, and applications of these theories to a wide range of biomolecular systems. Much of this
A Microcalorimeter and Bolometer Model
M. Galeazzi,D. McCammon
Physics , 2003, DOI: 10.1063/1.1559000
Abstract: The standard non-equilibrium theory of noise in ideal bolometers and microcalorimeters fails to predict the performance of real devices due to additional effects that become important at low temperature. In this paper we extend the theory to include the most important of these effects, and find that the performance of microcalorimeters operating at 60 mK can be quantitatively predicted. We give a simple method for doing the necessary calculations, borrowing the block diagram formalism from electronic control theory.
The Association of Tetrameric Acetylcholinesterase with ColQ Tail: A Block Normal Mode Analysis
Deqiang Zhang ,J. Andrew McCammon
PLOS Computational Biology , 2005, DOI: 10.1371/journal.pcbi.0010062
Abstract: Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChET]4–ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.
Kinetics of diffusion-controlled enzymatic reactions with charged substrates
Benzhuo Lu, J Andrew McCammon
BMC Biophysics , 2010, DOI: 10.1186/1757-5036-3-1
Abstract: PACS Codes: 82.45.Tv, 87.15.VvMSC Codes: 92C30Electrostatically steered diffusion-reaction processes exist widely in chemistry and biochemistry [1,2]. Ionic screening effects were first described by using the well-known Debye-Hückel limiting law (DHL) [3]. The DHL implemented within transition state theory [4] is still often used to estimate the kinetics of enzyme-substrate reactions. E.g., the dependence of the rate constant on ionic strength for the diffusion-controlled reaction of acetylcholine (charge = +1) catalyzed by acetylcholinesterase can be described approximately by [5]:where kon, and are second-order association rate constants at the specified ionic strength I, zero ionic strength, and infinite ionic strength, respectively. zE and zI are the charges of the enzyme and substrate involved in the interaction. The DHL says that the rate constant (in an electrostatically-steered process) decays exponentially with the increase of the square root of ionic strength, as is observed under some conditions [5-8]. However, because the DHL is based on an excess free energy described by the linearized Poisson-Boltzmann model of an ionic solution, it is assumed that the ionic species involved obey a Boltzmann distribution, i.e. are in an equilibrium state. The contributions of solute-solute interactions to the excess free energy are ignored in the theory. Moreover, in diffusion-influenced reactions, the substrate distribution is not in an equilibrium state. Therefore, the DHL only applies for low ionic strengths, and very dilute substrate concentrations. However, in real biological systems, the substrate concentration can be quite high; e.g., the acetylcholine concentration can reach about 300 mM when released from vesicles in synapses [9].The finite concentration effect was recently studied using Brownian dynamics simulation [10], and later theoretical work was done for the condition of weak substrate-substrate interaction or low substrate density [11]. Both works are
Substrate concentration dependence of the diffusion-controlled steady-state rate constant
J. Dzubiella,J. A. McCammon
Physics , 2004, DOI: 10.1063/1.1887165
Abstract: The Smoluchowski approach to diffusion-controlled reactions is generalized to interacting substrate particles by including the osmotic pressure and hydrodynamic interactions of the nonideal particles in the Smoluchoswki equation within a local-density approximation. By solving the strictly linearized equation for the time-independent case with absorbing boundary conditions, we present an analytic expression for the diffusion-limited steady-state rate constant for small substrate concentrations in terms of an effective second virial coefficient B_2*. Comparisons to Brownian dynamics simulations excluding HI show excellent agreement up to bulk number densities of B_2* rho_0 < 0.4 for hard sphere and repulsive Yukawa-like interactions between the substrates. Our study provides an alternative way to determine the second virial coefficient of interacting macromolecules experimentally by measuring their steady-state rate constant in diffusion-controlled reactions at low densities.
Molecular Dynamics of a kB DNA Element: Base Flipping via Cross-strand Intercalative Stacking in a Microsecond-scale Simulation
Cameron Mura,J. Andrew McCammon
Quantitative Biology , 2008, DOI: 10.1093/nar/gkn473
Abstract: The sequence-dependent structural variability and conformational dynamics of DNA play pivotal roles in many biological milieus, such as in the site-specific binding of transcription factors to target regulatory elements. To better understand DNA structure, function, and dynamics in general, and protein-DNA recognition in the 'kB' family of genetic regulatory elements in particular, we performed molecular dynamics simulations of a 20-base pair DNA encompassing a cognate kB site recognized by the proto-oncogenic 'c-Rel' subfamily of NF-kB transcription factors. Simulations of the kB DNA in explicit water were extended to microsecond duration, providing a broad, atomically-detailed glimpse into the structural and dynamical behavior of double helical DNA over many timescales. Of particular note, novel (and structurally plausible) conformations of DNA developed only at the long times sampled in this simulation -- including a peculiar state arising at ~ 0.7 us and characterized by cross-strand intercalative stacking of nucleotides within a longitudinally-sheared base pair, followed (at ~ 1 us) by spontaneous base flipping of a neighboring thymine within the A-rich duplex. Results and predictions from the us-scale simulation include implications for a dynamical NF-kB recognition motif, and are amenable to testing and further exploration via specific experimental approaches that are suggested herein.
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