Bjørn Gilbert Nielsen

Gauss-integral based representation of protein structure for predicting the fold class from the sequence

A representative subset of protein chains were selected from the CATH 2.4 database [C.A. Orengo, A.D. Michie, S. Jones, D.T. Jones, M.B. Swindells, J.M. Thornton, CATH-a hierarchic classification of protein domain structures, Structure 5 (8) (1997) 1093-1108], and were used for training a feed-forward neural network in order to predict protein fold classes by using as input the dipeptide frequency matrix and as output a novel representation of the protein chains in R^3^0 space, based on knot invariant values [P. Rogen, B. Fain, Automatic classification of protein structure by using Gauss integrals, Proceedings of the National Academy of Sciences of the United States of America 100 (1) (2003) 119-124; P. Rogen, H.G. Bohr, A new family of global protein shape descriptors, Mathematical Biosciences 182 (2) (2003) 167-181]. In the general case when excluding singletons (proteins representing a topology or a sequence homology as unique members of these sets), the success rates for the predictions were 77% for class level, 60% for architecture, and 48% for topology. The total number of fold classes that are included in the present data set (~500) is ten times that which has been reported in earlier attempts, so this result represents an improvement on previous work (reporting on a few handpicked folds). Furthermore, distance analysis of the network outputs resulting from singletons shows that it is possible to detect novel topologies with very high confidence (~85%), and the network can in these cases be used as a sorting mechanism that identifies sequences which might need special attention. Also, a direct measure of prediction confidence may be obtained from such distance analysis.

Calcium and the role of motoneuronal doublets in skeletal muscle control.

This work presents a novel structural model of skeletal muscle activation, providing a physiologically based account of frequency-dependent muscle responses like the catch-like effect. Numerous Ca2+ reservoirs within muscle fibers are considered, and a simplified analysis of the allocation of Ca2+ resources and the dynamics of calcium transport is proposed. The model correctly accounts for catch-like effects in slow and fast-twitch fibers during long-train stimulations and force–frequency relations in different muscle types. Results obtained from the model compare favorably to experiments showing that prolonged increases in force characteristic of the catch-like effect are not accompanied by sustained increases in free myoplasmic Ca2+. Also, in agreement with early experiments, the interspike interval in catch-inducing doublets is seen to be an important parameter for regulating the precise onset amplitude of the catch-like effect. This suggests that a plausible physiological function for the inclusion of doublets or the exclusion of individual spikes within a regular motor-neuronal spike-train is to rapidly bring skeletal muscles to predefined target forces according to prespecified motor programs in the central nervous system. This is a potentially very useful property directly mediated by the catch-like process modeled here. One further prediction of the model is that the slope of the frequency–tension profile of a given muscle is highly sensitive to changes in the efficiency and temporal characteristics of the dihydropyridine–ryanodine receptor complex. Interestingly, this is consistent with findings made on cardiac muscles, and might incidentally explain some instances of cardiac failure.

Unfolding transitions in myosin give rise to the double-hyperbolic force–velocity relation in muscle

This work presents an extension to a recent model of muscle contraction that was based on entropic elasticity (Nielsen 2002 J. Theor. Biol. 219 99–119). By using entropic elasticity as the origin of muscle force, various possibilities emerge that can account for the presence of the double-hyperbolic force–velocity relation in muscle that was observed by Edman (1988 J. Physiol. 404 301–21). In the present work, it will be argued that a slight change (elongation) of the contour length of the entropic springs involved in their high-force regions is sufficient to produce such a double-hyperbolic profile. A sudden elongation would correspond to an unfolding event of a small region of the myosin molecule, which causes a sudden reduction of the tension that may be produced by the individual molecule. To obtain the double-hyperbolic profile, it is assumed that a gradual transition occurs in the entropic spring array from being mainly composed of non-unfolded myosin springs that have a short (i.e. normal) contour length to consisting of a mixture of myosin springs with short and long (unfolded) contour lengths.

Sequence learning in differentially activated dendrites.

Differentially activated areas of a dendrite permit the existence of zones with distinct rates of synaptic modification, and such areas can be individually accessed using a reference signal which localizes synaptic plasticity and memory trace retrieval to certain subregions of the dendrite. It is proposed that the neural machinery required in such a learning/retrieval mechanism could involve the NMDA receptor, in conjunction with the ability of dendrites to maintain differentially activated regions. In particular, it is suggested that such a parcellation of the dendrite allows the neuron to participate in multiple sequences, which can be learned without suffering from the ‘wash-out’ of synaptic efficacy associated with superimposition of training patterns. This is a biologically plausible solution to the stability–plasticity dilemma of learning in neural networks.

The role of muscle spindles in constraining motor control

Abstract The functional importance of γ-motoneuronal activation during a simple movement task was explored using a computational model of a simplified neuromuscular system. Various schemes of γ-motoneuronal activation were tested under different task conditions. Analysis of the simulation data lend support to the idea that γ-motoneuron activity might be essential for cancelling expected stimuli rather than only for programming servo-controlled equilibrium positions of the limbs. It is concluded that the best performance of a movement is obtained when expected afference is cancelled by γ-activity, thereby allowing for a relatively pure and “noise-free” detection of unexpected loads.

Hydration shells exchange charge with their protein

Investigation of the interaction between a protein and its hydration shells is an experimental and theoretical challenge. Here, we used ultrasonic pressure waves in aqueous solutions of a protein to explore the conformational states of the protein and its interaction with its hydration shells. In our experiments, the amplitude of an ultrasonic pressure wave is gradually increased (0-20 atm) while we simultaneously measure the Raman spectra from the hydrated protein (β-lactoglobulin and lysozyme). We detected two types of spectral changes: first, up to 70% increase in the intensity of the fluorescence background of the Raman spectrum with a typical relaxation time of 30-45 min. Second, we detect changes in the vibrational Raman spectra. To clarify these results we conducted similar experiments with aqueous solutions of amino acids and ethanol. These experiments led us to conclude that, without the presence of an ultrasonic pressure, a protein and its hydration shells are in thermodynamic and charge equilibrium, i.e. a protein and its hydration shells exchange charges. The ultrasonic wave disrupts these equilibria which are regained within 30-45 min after the ultrasonic pressure is shut off.