A Model of Information Carried over a Neuron Soma.

A series of cellular automata models of amino acid side chains on a neuron soma membrane have been created to simulate their hydropathic influences on adjacent water molecules. The presence of pathways, referred to as water wires, is identified. These pathways are invoked as passage ways across a neuron soma of proton hopping carrying the information from dendrites to the axon hillock.

Effect of initial temperature on water aggregation at a cold surface.

Cellular automata models of water at two initial temperatures were created. Each model was exposed to a freezing surface. The formation of fully bonded water cells, f(4), was observed over time, beginning with a model of initially warm water and with initially cool water. The warm water formed more f(4) cells earlier than the initially cool water. A high percentage of f(4) cells is interpreted as the formation of ice. This is a model of the Mpemba effect. A description of the initial states for these two temperatures is offered in explanation of this effect.

Proton hopping: a proposed mechanism for myelinated axon nerve impulses.

Myelinated axon nerve impulses travel 100 times more rapidly than impulses in non-myelinated axons. Increased speed is currently believed to be due to 'hopping' or 'saltatory propagation' along the axon, but the mechanism by which impulses flow has never been adequately explained. We have used modeling approaches to simulate a role for proton hopping in the space between the plasma membrane and myelin sheath as the mechanism of nerve action-potential flow.

The creation of proton hopping from a drug-receptor encounter.

We extend recent modeling studies of proton hopping, used to describe the functioning of membrane channels and axon nerve conduction, to offer an explanation of the initiation of the nerve impulse at an effector-ligand encounter. This encounter is proposed to create a hydronium ion in the vicinity of the effector and ligand, which leads to a continuous flow of protons, called proton hopping, through water adjacent to this encounter. This proton hopping is proposed to be the message carried from the encounter to the axon of a particular nerve system associated with that particular effector-ligand system.

A cellular automata model of proton hopping down a channel.

Proton hopping is the process where a H-atom on a hydronium ion forms a H-bond with the O-atom of a neighboring H(2)O molecule. There is then an exchange of bonding forces when that covalent bond of the H-atom in the hydronium ion changes to a H-bond, and the previous H-bond changes to a covalent bond with the neighboring O-atom. The neighboring molecule now becomes a hydronium (H(3)O(+)) ion. This process repeats itself very rapidly among neighboring hydronium and H(2)O molecules. There is a flow of protonic character through bulk H(2)O, referred to as proton hopping. This process carries information through living systems where H(2)O is present. A cellular automata model of proton hopping down a channel has been created and studied. Variations in the rate of proton entry into the channel and the effects of the polar character of the channel walls was studied using the model. The behavior of the models corresponds to experimental results.

Modeling drug-induced anorexia by molecular topology.

Molecular topology (MT) has demonstrated to be a very good technique for describing molecular structures and to predict physical, chemical, and biological properties of compounds. In this paper, a topological-mathematical model based on MT has been developed for identifying drug compounds showing anorexia as a side effect. An external validation (test set) has been carried out, yielding over an 80% correct classification in the active and inactive compounds. These results reinforce the role of MT as a potential useful tool for predicting drug side effects.

A core process in receptor function, general anesthesia, sleep, and aging.

The diffusion of ligands and proteins was proposed to be guided by chreodes in water organized by protein-surface side chains with varying hydropathic states. These chreodes are proposed to be the target of volatile general anesthetic agents. The similarity between this effect and sleep deprivation leads to a proposal of an external agent responsible for sleep. This agent is elemental nitrogen. An extension of this effect is the concept that elemental nitrogen is a core factor in aging.

Proton Hopping in Living Systems.

This review focuses on the two-century-old concept of proton hopping. Introduced in 1806 by Grotthuss, it has evolved into an explanation of great diversity in describing many functions in living systems. It is a process involving water, which expands on the belief that life exists only in the presence of water. This review describes the mechanism of the process as it carries information through the water. A focus is initially made on the process of water in the nerve systems. The nature of the process in these systems is described as the passage of proton hopping in living systems. In drug-receptor encounters, proton hopping is initiated, carrying specific information from these specialized encounters. The review continues with an explanation of sleep, arising from an alteration in proton hopping. A similar phenomenon of the effect of general anesthetic agents is described, as they interfere with by proton hopping. Finally, memory functions are addressed in the realm of events carried by proton hopping.

Cellular automata models of the influences on solute diffusion through water.

A cellular automata (CA) model of liquid water has been used to study self-diffusion and the diffusion of a solute. The influences of temperature and solute hydropathic state are modeled as variables in this process. The self-diffusion model correlates very well with earlier experimental data. The diffusion of a solute experiences variation with temperature and its hydropathic states. These influences are found to relate to models of free hydroxy groups and the average cavity cluster size in bulk water. These preliminary models serve as the basis for modeling solute diffusion for specific contaminants of interest (such as heavy metals like uranium) in a water system, and addressing its migration patterns with water relative to temperature.

Models of solute aggregation using cellular automata.

A series of models using cellular automata (CA) are created to examine the influences on the phenomenon of solute aggregation. The models used the variations in hydropathic states of the solutes to produce changes in the clustering patterns. It was found that an increase in the hydrophobic character of the solute molecules led to greater aggregation. The effect of concentration of solutes was also modeled. These preliminary models of solute aggregation serve as the basis for subsequent models relative to both biological receptor interactions, and the fate and transport of environmental contaminants of interest.

Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of pyrazole derivatives as inhibitors of factor Xa and thrombin.

Factor Xa and thrombin, two critical pro-coagulant enzymes of the clotting cascade, are the primary target of current anticoagulation research that aims to develop potent, orally bioavailable, synthetic small-molecule inhibitors. To determine structural features that might play important roles in factor Xa and thrombin recognition and oral bioavailability, quantitative structure-activity and structure-property analyses were performed on the factor Xa and thrombin inhibition data and Caco-2 cell-permeability data of 3-substituted pyrazole-5-carboxamides reported by Pinto et al. (J. Med. Chem. 2001, 44, 566). The factor Xa and thrombin inhibition potencies, and Caco-2 cell permeability of the 3-substituted pyrazole-5-carboxamides could be quantitatively described through molecular connectivity and atom level E-state indices. Different quantitative structure-activity and structure-property models were derived for each of the three biological properties. The models are statistically relevant with correlation coefficients of at least 0.9, and contain only two or three molecular descriptor variables. The study demonstrates the use of molecular connectivity and E-state indices in understanding factor Xa and thrombin inhibition. In addition, the models may be useful for predictive purposes in generating molecules with better potency, specificity, and oral bioavailability.

A review of recent studies relating ligand diffusion, general anesthesia, and sleep.

This review article presents 3 theories related to ligand diffusion, general anesthesia and sleep. The first theory describes the diffusion of molecules across a protein surface to a receptor. It is based on the effect of the amino acid side chains on the protein surface on the structure of bulk water nearby. This influence creates pathways, called chreodes, through the water near the protein surface, permitting a rapid diffusion of molecules to the receptors. A second theory involving the role of chreodes presents a mechanism of action of nonspecific anesthetic agents. These agents interrupt the diffusion of neurotransmitter molecules to their receptors, bringing on the anesthetic effects. Finally, building on the similarities of anesthesia and sleep, a theory is presented proposing that an external agent influences sleep in a way similar to that of the nonspecific anesthetic molecules. This external agent is proposed to be elemental nitrogen. Several observations are presented to support this mechanism.

A cellular-automata model of the structure of bulk water.

Cellular-automata (CA) models of bulk water in the liquid state produce a series of patterns of the water structure, differing in the extent of binding of H(2)O molecules. The fractions of H(2)O molecules unbound, and those bound to one, two, three or four neighbors, designated f(0), f(1), f(2), f(3), and f(4), resp., become structural descriptors of water at various temperatures in the liquid state. The significance of these descriptors is challenged by examining their ability to correlate with a variety of physical properties. The quality of these relational equations demonstrates that the f(x) values present a structure alternative to the temperature (another physical property) in describing the structure of bulk water.

Water as a complex system: its role in ligand diffusion, general anesthesia, and sleep.

The work and inspiration of Robert Rosen is stated and expressed in personal tones. The concept of passages through water (H2O) near protein surfaces is reviewed in terms of its influence on ligand diffusion to an effector. This is offered as a target for interference by a non-specific general anesthetic agent. In view of the similarities between this anesthetic state and sleep, this mechanism is proposed to be operative for the sleep/wake states. Based on this mechanism and other factors, nitrogen (N2) is proposed as an exogenous sleep factor.

Cellular-automata models of solid-liquid interfaces.

A series of cellular-automata (CA) models have been created, simulating relationships between water (or aqueous solutions) and solid surfaces of differing hydropathic (i.e., hydrophilic or hydrophobic) nature. Both equilibrium- and dynamic-flow models were examined, employing simple breaking and joining rules to simulate the hydropathic interactions. The CA simulations show that water accumulates near hydrophilic surfaces and avoids hydrophobic surfaces, forming concave-up and concave-down meniscuses, resp., under equilibrium conditions. In the dynamic-flow simulations, the flow rate of water was found to increase past a wall surface as the surface became less hydrophilic, reaching a maximum rate when the solid surface was of intermediate hydropathic state, and then declining with further increase in the hydrophobicity of the surface. Solution simulations show that non-polar solutes tend to achieve higher concentrations near hydrophobic-wall surfaces, whereas other hydrophobic/hydrophilic combinations of solutes and surfaces do not show such accumulations. Physical interpretations of the results are presented, as are some possible biological consequences.

Nerve Conduction Through Dendrites via Proton Hopping.

BACKGROUND: In our previous studies of nerve conduction conducted by proton hopping, we have considered the axon, soma, synapse and the nodes of Ranvier. The role of proton hopping described the passage of information through each of these units of a typical nerve system. The synapse projects information from the axon to the dendrite and their associated spines. METHODS: We have invoked the passage of protons via a hopping mechanism to illustrate the continuum of the impulse through the system, via the soma following the dendrites. This is proposed to be a continuum invoked by the proton hopping method. RESULTS: With the proposal of the activity through the dendrites, via proton hopping, a complete model of the nerve function is invoked. At each step to the way, a water pathway is present and is invoked in the proposed model as the carrier of the message via proton hopping. The importance of the dendrites is evident by the presence of a vast number of spines, each possessing the possibility to carry unique messages through the nervous system. CONCLUSION: With this model of the role of dendrites, functioning with the presence of proton hopping, a complete model of the nerve system is presented. The validity of this model will be available for further studies and models to assess it's validity.

QSAR modeling of human serum protein binding with several modeling techniques utilizing structure-information representation.

Four modeling techniques, using topological descriptors to represent molecular structure, were employed to produce models of human serum protein binding (% bound) on a data set of 1008 experimental values, carefully screened from publicly available sources. To our knowledge, this data is the largest set on human serum protein binding reported for QSAR modeling. The data was partitioned into a training set of 808 compounds and an external validation test set of 200 compounds. Partitioning was accomplished by clustering the compounds in a structure descriptor space so that random sampling of 20% of the whole data set produced an external test set that is a good representative of the training set with respect to both structure and protein binding values. The four modeling techniques include multiple linear regression (MLR), artificial neural networks (ANN), k-nearest neighbors (kNN), and support vector machines (SVM). With the exception of the MLR model, the ANN, kNN, and SVM QSARs were ensemble models. Training set correlation coefficients and mean absolute error ranged from r2=0.90 and MAE=7.6 for ANN to r2=0.61 and MAE=16.2 for MLR. Prediction results from the validation set yielded correlation coefficients and mean absolute errors which ranged from r2=0.70 and MAE=14.1 for ANN to a low of r2=0.59 and MAE=18.3 for the SVM model. Structure descriptors that contribute significantly to the models are discussed and compared with those found in other published models. For the ANN model, structure descriptor trends with respect to their affects on predicted protein binding can assist the chemist in structure modification during the drug design process.

Proton Hopping as the Nerve Conduction Message.

BACKGROUND: The article proposes a new concept explaining nerve conduction information. The conduction is based upon proton hopping, the fastest known chemical reaction. A summary of the proton hopping at several parts of the nerve structure are described. METHODS: The details of each part of the nerve system are described in the article. RESULTS: A summary of the parts of the nerve structure involving the role of proton hopping, are expressed to give a complete picture of the nerve function and the role of proton hopping. CONCLUSION: An overall description of the function of the nerve is described in terms of the role of proton hopping as the mechanism of message passage.