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At least 1,603 records · Page 89Linked to original sources
PubMed2001

Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.

Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not changethe binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.

Antineoplastic Agents↗
PubMed2000

Computer modeling of force-induced titin domain unfolding.

Titin, a 1 micron long protein found in striated muscle myofibrils, possesses unique elastic and extensibility properties, and is largely composed of a PEVK region and beta-sandwich immunoglobulin (Ig) and fibronectin type III (FnIII) domains. The extensibility behavior of titin has been shown in atomic force microscope and optical tweezer experiments to partially depend on the reversible unfolding of individual Ig and FnIII domains. We performed steered molecular dynamics simulations to stretch single titin Ig domains in solution with pulling speeds of 0.1-1.0 A/ps, and FnIII domains with a pulling speed of 0.5 A/ps. Resulting force-extension profiles exhibit a single dominant peak for each domain unfolding, consistent with the experimentally observed sequential, as opposed to concerted, unfolding of Ig and FnIII domains under external stretching forces. The force peaks can be attributed to an initial burst of a set of backbone hydrogen bonds connected to the domains' terminal beta-strands. Constant force stretching simulations, applying 500-1000 pN of force, were performed on Ig domains. The resulting domain extensions are halted at an initial extension of 10 A until the set of all six hydrogen bonds connecting terminal beta-strands break simultaneously. This behavior is accounted for by a barrier separating folded and unfolded states, the shape of which is consistent with AFM and chemical denaturation data.

Amino Acid Sequence↗
PubMed2003

Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors.

Selective inhibition of nitric oxide synthase (NOS) isoforms has great therapeutic potential in the treatment of certain disease states arising from the pathological overproduction of nitric oxide. In this study three structures of each NOS isoform were employed to examine selective regions in the active site using the GRID/CPCA approach. In the GRID calculations, 10 probes covering hydrophobic, steric, and hydrogen-bond-acceptor and -donor interactions were used to calculate the molecular interaction fields (MIFs) in the active site. The side chain flexibility of the residues and the grid spacings were considered at the same time. Consensus principal component analysis (CPCA) was applied to analyze the MIFs differences in the active site between the NOS isoforms. By combining the cutout tool with GRID/CPCA pseudofield differential plots, several selective regions in the active site were identified. The selectivity analysis showed that the most important determinants for NOS inhibitor selectivity are hydrophobic and charge-charge interactions. Twenty-five inhibitors of NOS were then docked into the active site using the program AutoDock3.0. The regions identified as being important for selectivity by this method are in excellent agreement with inhibitor structure-activity relationships. A rational usage of the selective region described in this work should make it possible to develop NOS isoform-selective inhibitors.

Binding Sites↗
PubMed2006

[Computer modeling the hydrostatic pressure characteristics of the membrane potential for polymeric membrane, separated non-homogeneous electrolyte solutions].

On the basis of model equation depending the membrane potential deltapsis, on mechanical pressure difference (deltaP), concentration polarization coefficient (zetas), concentration Rayleigh number (RC) and ratio concentration of solutions separated by membrane (Ch/Cl), the characteristics deltapsis = f(deltaP)zetas,RC,Ch/Cl for steady values of zetas, RC and Ch/Cl in single-membrane system were calculated. In this system neutral and isotropic polymeric membrane oriented in horizontal plane, the non-homogeneous binary electrolytic solutions of various concentrations were separated. Nonhomogeneity of solutions is results from creations of the concentration boundary layers on both sides of the membrane. Calculations were made for the case where on a one side of the membrane aqueous solution of NaCl at steady concentration 10(-3) mol x l(-1) (Cl) was placed and on the other aqueous solutions of NaCl at concentrations from 10(-3) mol x l(-1) to 2 x 10(-2) mol x l(-1) (Ch). Their densities were greater than NaCl solution's at 10(-3) mol x l(-1). It was shown that membrane potential depends on hydrodynamic state of a complex concentration boundary layer-membrane-concentration boundary layer, what is controlled by deltaP, Ch/Cl, RC and zetas.

Biological Transport↗
PubMedDate not supplied

Computer modeling of the pathomechanics of spastic hip dislocation in children.

Spastic muscles about the hip cause subluxation, dislocation, and lead to acetabular dysplasia. Spastic hip disease occurs when the muscles about the hip exert forces that are too high or in the wrong direction or both. To determine the role of the hip forces in the progression of spastic hip disease and the effect of both muscle-lengthening and bony reconstructive surgeries, a computerized mathematical model of a spastic hip joint was created. The magnitude and direction of the forces of spastic hips undergoing surgery were analyzed preoperatively and postoperatively to determine which procedure is best suited for the treatment of spastic hip disease. The muscle-lengthening procedures included (a) the adductor longus, (b) the psoas, iliacus, gracilis, adductor brevis, and adductor longus, and (3) the psoas, iliacus, gracilis, adductor brevis, adductor longus, semimembranosus, and semitendinosus. The bony reconstructive and muscle-lengthening procedures included (a) lengthening the psoas, iliacus, gracilis, adductor brevis, adductor longus, semimembranosus, and semitendinosus combined with changing femoral neck anteversion from 45 to 10 degrees , (b) lengthening of the psoas, iliacus, gracilis, adductor brevis, adductor longus, semimembranosus, and semitendinosus combined with changing neck-shaft angle from 165 to 135 degrees , and (c) lengthening of the psoas, iliacus, gracilis, adductor brevis, adductor longus, semimembranosus, and semitendinosus combined with changing femoral neck anteversion from 45 to 10 degrees and neck-shaft angle from 165 to 135 degrees . Results show that a child with spastic hip disease has a hip-force magnitude 3 times that of the a child with a normal hip in the normal physiologic position. Based on this mathematical model the best to normalize the magnitude of the hip-joint reaction force, the muscles to be lengthened should include the psoas, iliacus, gracilis, adductor brevis, and the adductor longus. To normalize the direction of the hip force, the extremity should be positioned in the normal physiologic position. The impact of decreasing the femoral anteversion or femoral neck-shaft angle or both had little additional effect on the direction or magnitude of hip forces.

Biomechanical Phenomena↗
PubMed2001

Identification by integrated computer modeling and light scattering studies of an electrostatic serum albumin-hyaluronic acid binding site.

Dynamic light scattering and turbidimetry, carried out on solutions of hyaluronic acid (HA) and bovine or human serum albumin (SA) at fixed ionic strength (I), revealed a critical pH corresponding to the onset of HA-SA soluble complex formation. Subsequent reduction of pH below pH(c), corresponding to an increase in protein net positive charge, results in phase separation of the complex. The sensitivity of pH(c) to I indicated the primacy of electrostatic interactions in this process. Since pH(c) was always above the pK(a) of HA, these effects could be attributed to the influence of protein charge. The electrostatic potential around HSA was modeled using DelPhi (MSI) under pH, I conditions corresponding to incipient binding, phase separation, and noninteraction. At all incipient binding conditions (i.e., pH(c), at varying I), an identical region of positive potential 5 A from the protein van der Waals surface appeared. This unique domain intensified with a decrease in pH or I (corresponding to stronger binding), and diminished with an increase in pH or I (i.e., at noninteracting conditions). The size and low curvature of this domain could readily accommodate a 12 nm (decamer) sequence of HA. Simple electrostatic considerations indicate an electrostatic binding energy for the formation of this complex of ca. 1 kT, consistent with the condition of incipient complex formation. We suggest that such weak electrostatic binding may characterize nonspecific interactions for other protein-gylcosaminoglycan pairs.

Animals↗
PubMed2003

Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model.

Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 microl/min), the distribution of cytotoxicity in NK1 receptor-expressing neurons was predicted to reach an asymptotic limit at 6-8 h in the transverse direction at the level of the infusion cannula tip ( approximately 60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life approximately 60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.

Chronic Disease↗
PubMed1990

Computational modelling of motion detectors: responses to two-frame displays.

Schemes for motion detection fall into two classes. Reichardt correlators compare spatial luminance patterns at two locations at different times; gradient detectors compare spatial and temporal luminance gradients. Both are candidate operators for biological and machine vision systems. A large body of perceptual data exists, defining the properties of motion detectors used by human observers, which can form a basis for determining which class of detector is appropriate for the human visual system. Plausible versions of each detector were implemented, and their responses to a variety of two-frame stimuli were computed. Results indicated that both detectors can predict most of the data, but on balance gradient detectors offer the best working hypothesis for motion detection by human observers. This conclusion is necessarily limited to the type of stimuli used, and may require modification in the light of responses to continuously moving stimuli.

Humans↗
PubMed2006

[Computer modeling the dependences of the membrane potential for polymeric membrane separated non-homogeneous electrolyte solutions on concentration Rayleigh number].

On the basis of model equation describing the membrane potential delta psi(s) on concentration Rayleigh number (R(C)), mechanical pressure difference (deltaP), concentration polarization coefficient (zeta s) and ratio concentration of solutions separated by membrane (Ch/Cl), the characteristics delta psi(s) = f(Rc)(delta P, zeta s, Ch/Cl) for steady values of zeta s, R(C) and Ch/Cl in single-membrane system were calculated. In this system neutral and isotropic polymeric membrane oriented in horizontal plane, the non-homogeneous binary electrolytic solutions of various concentrations were separated. Nonhomogeneity of solutions is results from creations of the concentration boundary layers on both sides of the membrane. Calculations were made for the case where on a one side of the membrane aqueous solution of NaCl at steady concentration 10(-3) mol x l(-1) (Cl) was placed and on the other aqueous solutions of NaCl at concentrations from 10(-3) mol x l(-1) to 2 x 10(-2) mol x l(-1) (Ch). Their densities were greater than NaCl solution's at 10(-3) mol x l(-1). It was shown that membrane potential depends on hydrodynamic state of a complex concentration boundary layer-membrane-concentration boundary layer, what is controlled by deltaP, Ch/Cl, Rc and Zeta(s).

Computer Simulation↗
PubMed2003

Effect of external stresses on protein conformation: a computer modelling study.

The increasing use of digital technologies such as mobile phones has led to major health concerns about the effects of non-ionizing pulsed radiation exposure. We believe that the health implications of exposure to radiation cannot be fully understood without establishing the molecular mechanisms of biological effects of pulsed microwaves. We aim to establish methods for studying the molecular mechanisms of protein structural and energetic changes occurring due to external stresses related to non-ionizing radiation by using a combination of experimental and theoretical approaches. In this paper, we present the results from our fully atomistic simulation study of chemical and thermal stress response of a prototype protein, insulin. We performed a series of molecular dynamics simulations of insulin in solution under equilibrium conditions, under chemical stress (imitated by reducing the disulfide bonds in the protein molecule), and under short-lived thermal stress (imitated by increasing simulation temperature for up to 2 ns). The resultant protein conformational behaviour was analysed for various properties with the aim of establishing analysis routines for classification of protein unfolding pathways and associated molecular mechanisms.

Algorithms↗
PubMed2006

Porcine SPARC: isolation from dentin, cDNA sequence, and computer model.

Genes encoding the major enamel matrix proteins and non-collagenous proteins of bone and dentin are members of the secretory calcium-binding phosphoprotein (SCPP) family, which originated from ancestral SPARC (secreted protein, acidic and rich in cysteine; BM-40/osteonectin). To better understand the role of SPARC in mineralizing systems, we isolated SPARC from developing pig teeth, deduced its primary structure from the cDNA sequence, and determined its quaternary structure by homology modelling with reference to human SPARC crystal structures. The guanidine/EDTA extract from porcine dentin was fractionated by anion-exchange and size-exclusion chromatography. Stains-all positive bands at 38 and 35 kDa gave the N-terminal sequences APQQEALPDETEV and DFEKNYNMYIFPV, which corresponded to the SPARC N terminus and an internal region of the protein. Porcine SPARC contains 300 amino acids, including the 17-amino acid signal peptide, and shares 96.2% amino acid sequence identity with human SPARC. Without post-translational modifications, the 283-amino acid secreted protein has a molecular mass of 32.3 kDa. The three-dimensional model revealed that porcine SPARC contains a single N-linked glycosylation at N113, seven intramolecular disulfide bridges, and assembles into dimers. SPARC is composed of three structural/functional domains: an acidic Ca2+-binding, a follistatin-like, and an extracellular calcium-binding domain.

Amino Acid Sequence↗
PubMed2002

Visual event related potentials. The origin of wave P300. A computer model.

This five-layered model consisting of 180 neurons is aimed at simulating some elementary functions of primary visual cortex of mammals in form detection. Its main achievements are: 1. Detection of points, lines, simple geometric figures in the V1. 2. Abstraction of 19 different qualities of geometric figures. 3. Simulation and rational explanation of processing of peripheral stimuli in the V1, explanation of mechanism of origin of visual ERPs, including P300 wave. 4. Simulation and explanation of the nature and build up of the cognitive function within V1 and its possible relation to long-term memory. 5. The model is based partly on Hebb-type synapses, illustrates the role of neuronal assemblies, sheds light on the functional relationship of excitatory and inhibitory neurons, in their conformity with special tasks of different cortical layers.

Computer Simulation↗
PubMed1979

Metabolism of totally ischemic excised dog heart. II. Interpretation of a computer model.

Analysis of the ischemic dog heart preparation described in the preceding paper indicates that it is an analogue in slow motion of the tissue in the center of a cardiac infarct. It is respiring very slowly and not capable of performing mechanical work. Glycolysis starts up with both glucose and glycogen as inputs. Later hexokinase and to some extent phosphofructokinase become limiting owing to inhibitor accumulation or acidosis. Metabolism then results primarily from cAMP-driven glycogenolysis, largely limited by the glycogen debranching enzymes at later times, with accumultion not only of lactate and alpha-glycerophosphate but of glucose as well. Amino acid levels oscillate with time while fatty acids accumulate at late times. The elevation of cAMP at later times may involve disturbances in its metabolism as well as mechanisms such as adenosine accumulation that are more important in cardiac ischemia than in normal heart. The clinical implications of this behavior are discussed.

Amino Acids↗
PubMed1997

Speechreading and the structure of the lexicon: computationally modeling the effects of reduced phonetic distinctiveness on lexical uniqueness.

A lexical modeling methodology was employed to examine how the distribution of phonemic patterns in the lexicon constrains lexical equivalence under conditions of reduced phonetic distinctiveness experienced by speech-readers. The technique involved (1) selection of a phonemically transcribed machine-readable lexical database, (2) definition of transcription rules based on measures of phonetic similarity, (3) application of the transcription rules to a lexical database and formation of lexical equivalence classes, and (4) computation of three metrics to examine the transcribed lexicon. The metric percent words unique demonstrated that the distribution of words in the language substantially preserves lexical uniqueness across a wide range in the number of potentially available phonemic distinctions. Expected class size demonstrated that if at least 12 phonemic equivalence classes were available, any given word would be highly similar to only a few other words. Percent information extracted (PIE) [D. Carter, Comput. Speech Lang. 2, 1-11 (1987)] provided evidence that high-frequency words tend not to reside in the same lexical equivalence classes as other high-frequency words. The steepness of the functions obtained for each metric shows that small increments in the number of visually perceptible phonemic distinctions can result in substantial changes in lexical uniqueness.

Electronic Data Processing↗
PubMed1984

A very high affinity opioid binding site in rat brain: demonstration by computer modeling.

We present substantial new evidence for at least four distinct types of opioid receptors in rat brain, using quantitative ligand binding studies and mathematical modeling. Three of these binding sites are consistent with the well established "mu", "delta" and "kappa" receptors. The fourth has two distinctive features: 1) extremely high affinity (dissociation constant less than 1 nM); 2) almost complete lack of specificity for the classical "delta" or "mu" selective ligands. These properties are consistent with the putative "mu1" receptor described by Pasternak and coworkers.

Animals↗
PubMed2002

Structure-based design of a novel peptide inhibitor of HIV-1 integrase: a computer modeling approach.

The insertion of viral DNA into the host chromosome is an essential step in the replication of HIV-1, and is carried out by an enzyme, HIV-1 integrase (IN). Since the latter has no human cellular counterpart, it is an attractive target for antiviral drug design. Several IN inhibitors having activities in the micromolar range have been reported to date. However, no clinically useful inhibitors have yet been developed. Recently reported diketo acids represent a novel and selective class of IN inhibitors. These are the only class which appear to selectively target integrase and two of the inhibitors, L-708,906 and L-731,988, are the most potent inhibitors of preintegration complexes described to date. The X-ray crystal structure of the IN catalytic domain complexed with a diketo acid derivative inhibitor, 5CITEP, has recently been determined. Although the structure is of great value as a platform for drug design, experimental data suggest that crystal packing effects influence the observed inhibitor position. This has been confirmed by computational docking studies using the latest version (3.0) of the AutoDock program, which has been shown to give results largely consistent with available experimental data. Using AutoDock 3.0 and SYBYL6.6 we have modeled the complexes of IN with the diketo acid inhibitors so as to identify the enzyme binding site. In the quest for novel, potent and selective small molecule inhibitors, we present here a new approach to peptide inhibitor design using a, b- unsaturated (dehydro) residues, which confer a unique conformation on a peptide sequence. Based on the above models, we selected a tetrapeptide sequence containing a dehydro-Phe residue, which was found to have an open conformation as ascertained from its X-ray crystal structure. Docking results on this peptide led us to propose a modification at the C-terminal end. The modified peptide was found to dock in a similar position as the diketo acid inhibitors and was predicted to have a comparable potency.

Acetoacetates↗
PubMed1992

Blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients: prediction by computer modeling.

To establish a qualitative and quantitative model of blood glucose response to stress hormone exposure, healthy subjects (HS) on and off somatostatin (250 micrograms/h) as well as insulin dependent diabetic patients were infused with either epinephrine (E), glucagon (G), cortisol (F), growth hormone (GH) or with a cocktail of these hormones raising plasma stress hormones to values seen in severe diabetic ketoacidosis. The developed input/output model consists of two submodels interconnected in series plus two additional submodels for correction of gains describing both sensitivity of tissue response and utilisation as well as provision of glucose. It was shown and confirmed experimentally that blood glucose response to stress hormones was essentially nonlinear. Furthermore, the mathematical models for healthy subjects and for insulin dependent diabetic patients proved to be of the same structure and differed only in the values of some typical parameters. The model raises the possibility to describe and in part to predict blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients.

Adult↗
PubMed1988

[Computation of low-risk compression. Computation model and results of experimental decompression research].

1. The relationship between tolerated nitrogen oversaturation and ambient pressure is practically linear. 2. Tissues with short half-times have a higher tolerance than tissues with long half-times. 3. The human body can be regarded as consisting of 16 compartments with half-times from 4 to 635 minutes for nitrogen and from 1.5 to 240 minutes for helium. 4. The coefficients for calculation of minimal tolerated ambient pressure for a given PN2 in the tissue can be deduced directly from the half-times for nitrogen. 5. The results of 573 simulated air dives and 544 real dives in mountain lakes are in accordance with the computed limits of tolerance. 6. The ZH-L16 system is applicable to all exposures with air or oxygen-nitrogen mixtures. 7. Adaptation to breathing of oxy-helium or trimix is simple.

Atmospheric Pressure↗