Showing papers by "Michael Levitt published in 2001"

Quantification of the hydrophobic interaction by simulations of the aggregation of small hydrophobic solutes in water

Abstract: The hydrophobic interaction, the tendency for nonpolar molecules to aggregate in solution, is a major driving force in biology. In a direct approach to the physical basis of the hydrophobic effect, nanosecond molecular dynamics simulations were performed on increasing numbers of hydrocarbon solute molecules in waterfilled boxes of different sizes. The intermittent formation of solute clusters gives a free energy that is proportional to the loss in exposed molecular surface area with a constant of proportionality of 45 6 6 calymolzA 2 . The molecular surface area is the envelope of the solute cluster that is impenetrable by solvent and is somewhat smaller than the more traditional solvent-accessible surface area, which is the area transcribed by the radius of a solvent molecule rolled over the surface of the cluster. When we apply a factor relating molecular surface area to solvent-accessible surface area, we obtain 24 calymolzA 2 . Ours is the first direct calculation, to our knowledge, of the hydrophobic interaction from molecular dynamics simulations; the excellent qualitative and quantitative agreement with experiment proves that simple van der Waals interactions and atomic point-charge electrostatics account for the most important driving force in biology.

The birth of computational structural biology.

Abstract: Like Sydney Altman 1 , I too was initially rejected by the renowned Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, England. The year was 1967 and I was then in my final year of a B.Sc. degree in Physics at Kings College in London. Enthralled by John Kendrew's BBC 1964 television series \" The Thread of Life \" , I wanted desperately to do my Ph.D. at the MRC in Cambridge. Alas there was no room for any new postgraduate students in 1967! After some negotiations, I was accepted for the following year. More importantly, John Kendrew said that I should spend the intervening period at the Weizmann Institute in Israel with Shneior Lifson. Kendrew had just heard of Lifson's initial ideas 2 on the consistent force field (CFF), which was an attempt to simulate the properties of any molecular system from a simple potential energy function. He believed that these methods should be applied to protein and nucleic acid macro-molecules. I arrived in Israel in October, 1967 and set to work programming the consistent force field under the supervision of Lifson and his Ph.D. student Arieh Warshel. At that time, computing at the Weizmann Institute was amongst the best in the world; in 1963 computer engineers there had built their own machine, appropriately known as the Golem, after the Jewish folklore automaton. In a few short months we had a program called CFF that allowed us to calculate the energy, forces (energy first derivatives with respect to atomic positions) and curvature (energy second derivatives with respect to atomic positions) of any molecular system. Warshel went on to use the program to calculate structural, thermodynamic and spectroscopic properties of small organic molecules 3 , while I followed Kendrew's dictum and applied these same programs to proteins. This led to the first energy minimization of an entire protein structure (in fact we did two, myoglobin and lysozyme) in a process that became known as energy refinement 4. I began my Ph.D. at the MRC in Cambridge in September, 1968 and was immediately immersed in the annual tradition of Lab Talks. These talks by members of the three divisions at the Laboratory of Molecular Biology at that time (Structural Studies Division under Kendrew, the Cell Biology Division under Sydney Brenner and Francis Crick, and Protein and Nucleic Acid Chemistry Division under Fred Sanger) were a treat for newcomers to …

Gas production by feces of infants.

Abstract: Background: Intestinal gas is thought to be the cause abdominal discomfort in infants. Little is known about the type and amount of gas produced by the infant's colonic microflora and whether diet influences gas formation. Methods: Fresh stool specimens were collected from 10 breast-fed infants, 5 infants fed a soy-based formula, and 3 infants fed a milk-based formula at approximately 1, 2, and 3 months of age. Feces were incubated anaerobically for 4 hours at 37°C followed by quantitation of hydrogen (H 2 ), methane (CH 4 ), carbon dioxide (CO 2 ), hydrogen sulfide (H 2 S), methanethiol (CH 3 SH), and dimethyl sulfide (CH 3 SCH 3 ) in the headspace. Results: H 2 was produced in greater amounts by breast-fed infants than by infants in either formula group, presumably the consequence of incomplete absorption of breast milk oligosaccharides. CH 4 was produced in greater amounts by infants fed soy formula than by infants on other diets. CO 2 was produced in similar amounts by infants in all feeding groups. Production of CH 3 SH was conspicuously low by feces of breast-fed infants and production of H 2 S was high by soy-formula-fed infants. CH 3 SCH 3 was not detected. Only modest changes with age were observed and there was no relation between gas production and stool consistency, although stools were more likely to be malodorous when concentrations of H 2 S and/or CH 3 SH were high. Conclusions: Gas release by infant feces is strongly influenced by an infant's diet. Of particular interest are differences in production of the highly toxic sulfur gases, H 2 S and CH 3 SH. because of the role that these gases may play in certain intestinal disorders of infants.

Spontaneous Fluctuations in the Concentrations of Oral Sulfur-containing Gases

Abstract: Breath hydrogen sulfide (H2S) and methyl-mercaptan (CH3SH) concentrations are used as quantitative indicators of halitosis. However, measurements of these gases in duplicate oral samplings often show poor reproducibility. To determine if this poor reproducibility is an artifact of the collection/analytical procedure or a true biological phenomenon, we used a standardized technique to collect from 20 to 30 oral gas samples at two-minute intervals from 11 healthy subjects. The samples were analyzed for sulfur gases and CO2. Sizable variations in H2S and CH3SH concentrations were not associated with alterations in CO2, indicating that the variations did not reflect variable contamination with atmospheric or pulmonary gas. In addition, fluctuations in H2S and CH3SH were not identical and often were not random. We conclude that minute-to-minute variability in oral sulfur gas concentrations is a true biological phenomenon. This fluctuation complicates experimental studies designed to show that interventions alter halitosis.

Determination of optimal Chebyshev-expanded hydrophobic discrimination function for globular proteins

Abstract: We describe the development of a scoring function designed to model the hydrophobic effect in protein folding. An optimization technique is used to determine the best functional form of the hydrophobic potential. The scoring function is expanded using the Chebyshev polynomials, for which the coefficients are determined by minimizing the Z-score of native structures in the ensembles of alternate conformations. (The Z-score is the score relative to the mean, measured in units of standard deviation.) The derived effective potential is tested on decoy sets conventionally used in such studies. The function is able to discriminate very well between correct and incorrect folds, despite the fact that it simply counts the number of neighbors of each amino acid. Our results show that the techniques of Z-score optimization and Chebyshev expansion work, and work well. Our results also confirm that hydrophobic effect is one of the principal driving forces in protein folding.