Nonlinear elasticity, proteinquakes, and the energy landscapes of functional transitions in proteins.

Large-scale motions of biomolecules involve linear elastic deformations along low-frequency normal modes, but for function nonlinearity is essential. In addition, unlike macroscopic machines, biological machines can locally break and then reassemble during function. We present a model for global structural transformations, such as allostery, that involve large-scale motion and possible partial unfolding, illustrating the method with the conformational transition of adenylate kinase. Structural deformation between open and closed states occurs via low-frequency modes on separate reactant and product surfaces, switching from one state to the other when energetically favorable. The switching model is the most straightforward anharmonic interpolation, which allows the barrier for a process to be estimated from a linear normal mode calculation, which by itself cannot be used for activated events. Local unfolding, or cracking, occurs in regions where the elastic stress becomes too high during the transition. Cracking leads to a counterintuitive catalytic effect of added denaturant on allosteric enzyme function. It also leads to unusual relationships between equilibrium constant and rate like those seen recently in single-molecule experiments of motor proteins.

Different scenarios for inter-protein electron tunneling: the effect of water-mediated pathways.

Recent theoretical developments now allow for reliable calculation oftunneling matrix elements in unimolecular biological electron transferreactions that have been tested experimentally. Most biological ETprocesses, however, are bimolecular, or involve large-scale proteindomain motions. In this paper, initial advances in this direction bystudying the inter-protein electron transfer between cytochrome c(2)andthe photosynthetic reaction center. Utilizing an approach that integratesmolecular dynamics and the Pathways method, we have observed that theensemble dominant tunneling pathways in this reaction go though thetyrosine 162 or are water mediated.

Vibrational energy transfer in a protein molecule.

Mode coupling in a protein molecule was studied by a molecular dynamics simulation of the intramolecular vibrational energy transfer in myoglobin at near zero temperature. It was found that the vibrational energy is transferred from a given normal mode to a very few number of selective normal modes. These modes are selected by the relation between their frequencies, like Fermi resonance, governed by the third order mode coupling term. It was also confirmed that the coupling coefficients had high correlation with how much the coupled modes geometrically overlapped with each other.

Molecular dynamics simulation shows large volume fluctuations of proteins.

In this paper we present a new approach to study the volume fluctuations of proteins. From a 1 ns molecular dynamics simulation, the volume fluctuation of human lysozyme has been calculated. We used two different ways for the calculation. In the first one, the volume fluctuation is extracted directly from the trajectory. For the second one, a newly developed formalism based on principal component analysis is used. The r.m.s. volume fluctuations obtained from the two analyses agree well with each other. The isothermal intrinsic compressibility was found to be larger than the one reported by experiment. The difference is discussed and suggested to exist in the assumed uncertainty of the compressibility of hydrated water to deduce the isothermal intrinsic compressibility from the experimental value. Spectral analysis shows that low-frequency dynamics dominate the total volume fluctuation. The same aspect is found in the study using principal component analysis. This low-frequency region is related to large and slow motions of proteins. Therefore a long time dynamics simulation is necessary to describe the volume fluctuations of proteins.

[A study of ambulatory treatment for pulmonary tuberculosis in foreigners residing in Japan].

We studied 130 cases of pulmonary tuberculosis in foreigners residing in Japan to obtain the results as follows; 1. Of the cases of pulmonary tuberculosis in foreigners who are registered and receiving treatment in Japan, 20.3% were treated at three dispensaries of the Japan Antituberculosis Association in Tokyo. 2. The nationality of the cases treated was China in more than half of them, followed by the Republic of Korea. 3. The number of days taken from entry into Japan to the start of treatment was about 11.4 months; 0.9% of the total number of cases examined by chest radiophotography required medical treatment. 4. Their living conditions in Japan according to questionnairing are: 56.2% have jobs in Japan; working hour, 4.99 +/- 1.19 hours a day; 64.4% take night work; 57.6% work in food/drink service industry; living space is 12.5 m2; 52.4% share the same house with other persons, living together with 1.6 persons. 5. As for the type of illness at the start of treatment, GAKKAI classification type III accounted for 90% and spread 1 83.8%. GAKKAI classification type II accounted for 10%, consisting of many relatively mild cases. 6. The defaulter rate was high at 40.8%. The reason for defaulting was broken down to discontinuation on his own 68%, repatriation 15% and side-effects 19%. The time to default was average 3.2 +/- 3.1 months after the start of treatment. They defaulted 1.2 +/- 0.4 times on the average. 7. To reduce the defaulter rate to the minimum in treating the foreigners residing in Japan, the following may be needed. a. To give guidance on the regimen including the need of treatment and risk associated with discontinuation of treatment at the first visit. b. Measures to reduce the amount to be born by the individual in the medical expenses. c. Preparation of a pamphlet for therapeutic guidance in foreign languages.

Effects of methamphetamine administration on brain neurotensin-like immunoreactivity in rats.

The effects of methamphetamine (MAP) administration on neurotensin-like immunoreactivity (NTLI) were investigated in the rat brain. A single administration of MAP induced dose-dependent and reversible increases in NTLI in the caudate-putamen, limbic forebrain and midbrain. NTLI in the caudate-putamen, limbic forebrain and midbrain was also enhanced after repeated administration of MAP. It was assumed that MAP enhanced NTLI in the caudate-putamem, limbic forebrain and midbrain through its action upon the nigrostriatal and mesolimbic dopamine systems.

Serial DST, TRH test, and TRH-like immunoreactivity measurements in major affective disorders.

Neuroendocrine functions in depressed patients with major affective disorders were serially investigated by the Dexamethasone Suppression Test (DST), the thyrotropin-releasing hormone (TRH) stimulation test, and the plasma TRH-like immunoreactivity (TRH-LI) measurement. Prior to antidepressant therapy, the sensitivity for nonsuppression to the DST was 36.0%, whereas that for blunted thyroid-stimulating hormone (TSH) response to TRH was 28.0%. Both DST nonsuppression and TSH blunting appeared to be state-related markers for depressed patients. Specifically, a significant increase of maximum TSH response to TRH after 4 weeks of antidepressant therapy was associated with clinical improvement. Plasma TRH-LI in depressed patients was significantly lower than that of healthy controls. It is possible that the lower plasma TRH-LI level is related to the pathophysiology of some depressed patients with major affective disorders.

Isolation and characterization of a new aristeromycin analog.

The chemical structure of aristeromycin M, a new carbocyclic nucleoside, was elucidated by spectroscopic analysis and chemical transformation from aristeromycin.

Effects of phencyclidine administration on behavior and brain neurotensin-like immunoreactivity in rats.

The effects of acute and chronic phencyclidine (PCP) administration on neurotensin-like immunoreactivity (NTLI) were investigated in discrete regions of rat brain. Both acute and chronic administration of PCP induced high locomotor activity, stereotypy and ataxia. On PCP administration, NTLI decreased significantly in the frontal cortex (Fc) alone. These results suggest that the decrease in NTLI in Fc is related to the behavioral abnormalities produced by PCP.

Protected 2'-deoxyaristeromycin on polymer support: a substitute for the acid labile 2'-deoxyadenosine moiety at the 3'-terminus of oligodeoxynucleotides.

A modified nucleoside antibiotic on polymer support was employed in the solid-phase synthesis of two oligodeoxynucleotides to substitute acid labile 2'-deoxyadenosine(A) at the 3'-terminus of oligomers with acid resistant 2'-deoxyaristeromycin(Ar). The duplex of the decamer having sticky ends was inserted successfully into the Eco R1 site of pBR322. E. coli DH 1 was transformed with the Ar-containing plasmid. Inspection of the cloned plasmid pBR2552 by restriction endonucleases revealed that no deletion and insertion occurred near the inserted sequence. This result indicates that Ar can behave as A in DNA replication of the host cells. Therefore, Ar can be used as a substitute for 3'-terminal A in the solid-phase oligonucleotide synthesis.