We describe MUSCLE, a new computer program for creating multiple alignments of protein sequences. Elements of the algorithm include fast distance estimation using kmer counting, progressive alignment using a new profile function we call the logexpectation score, and refinement using treedependent restricted partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank in accuracy on each of these sets. Without refinement, MUSCLE achieves average accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the fastest of the tested methods for large numbers of sequences, aligning 5000 sequences of average length 350 in 7 min on a current desktop computer. The MUSCLE program, source code and PREFAB test data are freely available at http://www.drive5. com/muscle.

MUSCLE: multiple sequence alignment with high accuracy and high throughput

CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.

CHARMM: A program for macromolecular energy, minimization, and dynamics calculations

For a successful analysis of the relation between amino acid sequence and protein structure, an unambiguous and physically meaningful definition of secondary structure is essential. We have developed a set of simple and physically motivated criteria for secondary structure, programmed as a pattern-recognition process of hydrogen-bonded and geometrical features extracted from x-ray coordinates. Cooperative secondary structure is recognized as repeats of the elementary hydrogen-bonding patterns “turn” and “bridge.” Repeating turns are “helices,” repeating bridges are “ladders,” connected ladders are “sheets.” Geometric structure is defined in terms of the concepts torsion and curvature of differential geometry. Local chain “chirality” is the torsional handedness of four consecutive Cα positions and is positive for right-handed helices and negative for ideal twisted β-sheets. Curved pieces are defined as “bends.” Solvent “exposure” is given as the number of water molecules in possible contact with a residue. The end result is a compilation of the primary structure, including SS bonds, secondary structure, and solvent exposure of 62 different globular proteins. The presentation is in linear form: strip graphs for an overall view and strip tables for the details of each of 10.925 residues. The dictionary is also available in computer-readable form for protein structure prediction work.

Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features

6.2.2. Definition of Effective Properties 3064 6.3. Response Properties to Magnetic Fields 3066 6.3.1. Nuclear Shielding 3066 6.3.2. Indirect Spin−Spin Coupling 3067 6.3.3. EPR Parameters 3068 6.4. Properties of Chiral Systems 3069 6.4.1. Electronic Circular Dichroism (ECD) 3069 6.4.2. Optical Rotation (OR) 3069 6.4.3. VCD and VROA 3070 7. Continuum and Discrete Models 3071 7.1. Continuum Methods within MD and MC Simulations 3072

/pdf/quantum-mechanical-continuum-solvation-models-3edv963g14.pdf

Quantum mechanical continuum solvation models.

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

/pdf/gromacs-fast-flexible-and-free-15aazpel5u.pdf

GROMACS: Fast, flexible, and free

While about 50 million Americans malabsorb lactose, the colonic metabolism of this disaccharide may prevent the symptomatic state known as lactose intolerance. Elucidation of the clinical importance of lactose malabsorption requires comparison of symptoms after ingestion of lactose with those following an identical appearing lactose-free control. This paper reviews the extensive literature concerning lactose-induced symptoms and the value of lactose digestive aids. Poorly controlled studies have suggested that a cup of milk results in appreciable symptoms in the majority of lactase-deficient subjects. In contrast, controlled trials in unselected lactose malabsorbers of subjects claiming severe lactose intolerance indicate that symptoms from a cup of milk are no greater than that with a lactose-hydrolyzed control. An increasing fraction of subjects experience symptoms as the lactose load is increased, with the majority having symptoms when the equivalent of 1 L of milk is ingested as a single dose. Further studies are required to determine the tolerance to several cups of milk taken throughout the day. Available digestive aids include pre-hydrolyzed milk and lactase preparations that can be added to milk (which is then incubated) or ingested with milk. While these products are effective in reducing symptoms, it should be emphasized that there appears to be no need for these preparations when the dosage of milk is limited to one cup per day.

Review article: the treatment of lactose intolerance.

We investigated three possible causes of the increased ratio of amylase/creatinine clearance observed in acute pancreatitis. The presence of rapidly cleared isoamylase was excluded by studies of serum and urine, which demonstrated no anomalous isoamylases. In pancreatitis, the ratios (±1 S.E.M.) of both pancreatic isoamylase (9.2±0.6 per cent) and salivary isoamylase (8.6±1.6 per cent) were significantly (P<0.01) elevated over respective control values (2.4±0.2 and 1.8±0.2 per cent). Increased glomerular permeability to amylase was excluded by the demonstration of normal renal clearance of dextrans. We tested tubular reabsorption of protein by measuring the renal clearance of β2-microglobulin, which is relatively freely filtered at the glomerulus and then avidly reabsorbed by the normal tubule. During acute pancreatitis the ratio of the renal clearance of β2-microglobulin to that of creatinine was 1.22±0.52 per cent, an 80-fold increase over normal (0.015±0.002 per cent), with a rapid return towa...

Mechanism of Increased Renal Clearance of Amylase/Creatinine in Acute Pancreatitis

An approach to construct low resolution models of protein structure from sequence information using a combination of different methodologies is described. All possible compact self-avoiding C alpha conformations (approximately 10 million) of a small protein chain were exhaustively enumerated on a tetrahedral lattice. The best scoring 10,000 conformations were selected using a lattice-based scoring function. All-atom structures were then generated by fitting an off-lattice four-state phi/psi model to the lattice conformations, using idealised helix and sheet values based on predicted secondary structure. The all-atom conformations were minimised using ENCAD and scored using a second hybrid scoring function. The best scoring 50, 100, and 500 conformations were input to a consensus-based distance geometry routine that used constraints from each the conformation sets and produced a single structure for each set (total of three). Secondary structures were again fitted to the three structures, and the resulting structures were minimised and scored. The lowest scoring conformation was taken to be the "correct" answer. The results of application of this method to twelve proteins are presented.

http://psb.stanford.edu/psb-online/proceedings/psb99/Samudrala.pdf

A combined approach for ab initio construction of low resolution protein tertiary structures from sequence.

Absorption of calcium from milk and yogurt.

Highly toxic sulfur-containing gases have been pathogenetically implicated in ulcerative colitis. Utilizing a rat model, we studied the production and elimination of sulfur-containing gases within ...

Michael Levitt

Papers

Review article: the treatment of lactose intolerance.

Mechanism of Increased Renal Clearance of Amylase/Creatinine in Acute Pancreatitis

A combined approach for ab initio construction of low resolution protein tertiary structures from sequence.

Absorption of calcium from milk and yogurt.

Production and elimination of sulfur-containing gases in the rat colon