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PubMed1997

Optimisation of mammographic breast cancer screening using a computer simulation model.

To optimise breast cancer screening protocols, risk (induction of fatal tumors) versus benefit (reduction in the number of fatal tumors) analyses are performed for a simulated stable Swedish female population, using the Model for evaluation of Breast cancer Screening (MBS). The present study comprises, the influences of various screening parameters, i.e. ages at which screening is started and stopped, interval period between successive sessions, tumor detection limits for screening and average glandular dose per screening session. When the results of the present study are expressed in terms of numbers of fatal breast tumors, it appears that starting and stopping ages for screening of 40 and 80 years, respectively, seem realistic. An increased screening frequency results in a larger reduction of breast cancer mortality. This reduction is significant for ages between 40 and 51 years but only marginal for ages above 70 years. High resolution screening, i.e., the detection of tumors at smaller size, results in a larger benefit but does not indicate a younger age for starting of screening. The average glandular dose per screening session does only influence the risks of screening. As separate risk and benefit results are presented, a change in average glandular dose on the total effect of screening can easily be calculated.

Adult↗

PubMed1999

Activation mechanism of human oxytocin receptor: a combined study of experimental and computer-simulated mutagenesis.

The aim of this study was to investigate the molecular changes associated with the transition of the human oxytocin receptor from its inactive to its active states. Mutation of the conserved arginine of the glutamate/aspartate-arginine-tyrosine motif located in the second intracellular domain gave rise to the first known constitutively active oxytocin receptor (R137A), whereas mutation of the aspartic acid located in the second transmembrane domain led to an inactive receptor (D85A). The structural features of the constitutively active and inactive receptor mutants were compared with those of the wild type in its free and agonist-bound states. The results suggest that, although differently triggered, the activation process induced by the agonist and the activating mutation are characterized by the opening of a solvent exposed site formed by the 2nd intracellular loop, the cytosolic extension of helix 5, and the 3rd intracellular loop; on the contrary, the D85A mutation prevents oxytocin from triggering the opening of a cytosolic site. On the basis of these findings, we hypothesize that this cytosolic crevice plays an important role in G protein recognition. Finally, comparative analysis of the free- and agonist-bound forms of the wild-type oxytocin receptor and alpha1B adrenergic receptor suggests that the highly conserved polar amino acids and the seven helices play similar mechanistic roles in the different G protein-coupled receptors.

Amino Acid Sequence↗

PubMed2006

Incremental retinal-defocus theory of myopia development--schematic analysis and computer simulation.

Previous theories of myopia development involved subtle and complex processes such as the sensing and analyzing of chromatic aberration, spherical aberration, spatial gradient of blur, or spatial frequency content of the retinal image, but they have not been able to explain satisfactorily the diverse experimental results reported in the literature. On the other hand, our newly proposed incremental retinal-defocus theory (IRDT) has been able to explain all of these results. This theory is based on a relatively simple and direct mechanism for the regulation of ocular growth. It states that a time-averaged decrease in retinal-image defocus area decreases the rate of release of retinal neuromodulators, which decreases the rate of retinal proteoglycan synthesis with an associated decrease in scleral structural integrity. This increases the rate of scleral growth, and in turn the eye's axial length, which leads to myopia. Our schematic analysis has provided a clear explanation for the eye's ability to grow in the appropriate direction under a wide range of experimental conditions. In addition, the theory has been able to explain how repeated cycles of nearwork-induced transient myopia leads to repeated periods of decreased retinal-image defocus, whose cumulative effect over an extended period of time results in an increase in axial growth that leads to permanent myopia. Thus, this unifying theory forms the basis for understanding the underlying retinal and scleral mechanisms of myopia development.

Animals↗

PubMed2001

Effect of policies directed at youth access to smoking: results from the SimSmoke computer simulation model.

OBJECTIVES: To develop a simulation model to predict the effects of youth access policies on retail compliance, smoking rates, and smoking attributable deaths. METHODS: A model of youth access policies is developed based on empirical research and a theory of perceived risk. The model incorporates substitution into other sources as retail sales are restricted, and is used to project the number of smokers and smoking related deaths. Various policies to limit youth access to cigarettes are evaluated, and we explore how efficient policies may be developed. RESULTS: The model predicts that a well designed and comprehensive policy that includes sufficient compliance checks, penalties, and community involvement has the potential to reduce the number of young smokers. Because smoking related deaths occur later in life, the effects on health are largely delayed. CONCLUSIONS: A well designed youth access policy has the ability to affect youth smoking rates in the short term, and will lead to savings in lives in future years. The ability of retail oriented policies to reduce youth smoking, however, is limited. Other tobacco control policies, including those directed at non-retail sources of cigarettes, are also needed.

Adolescent↗

PubMedDate not supplied

Computational simulation of flow in the end-to-end anastomosis of a rigid graft and a compliant artery.

Implanted vascular grafts often fail because of the development of intimal hyperplasia in the anastomotic region, and compliance mismatch between the host artery and graft exacerbates the problem. This study focused on the effects of radial artery wall motion and phase angle between pressure and flow waves (impedance phase angle [IPA]) on the wall shear rate (WSR) behavior near end-to-end vascular graft anastomoses models connecting rigid grafts and compliant arteries. A finite element model with transient flow and moving boundaries was set up to simulate oscillatory flow through a 16% undersized (mean) diameter graft model. During the simulations, different artery diameter variations (DVs) over a cycle (DV) and IPAs were simulated in the physiologic range for an oscillatory flow (mean Re = 150, peak Re = 300, unsteadiness parameter alpha = 3.9). The results show that for normal physiologic conditions (DV = 6%, IPA = -45 degrees) in a 16% undersized graft, the minimum distal mean WSR is reduced by 60% compared to steady flow at the mean Re; the minimum distal WSR amplitude increases 50% when IPA changes from -5 degrees to -85 degrees, and increases 60% when DV changes from 2% to 10%. This indicates that compliance mismatch induces lower mean WSR and more oscillatory WSR in the distal anastomotic region, which may contribute to intimal hyperplasia. In addition, the convergent-divergent geometry of the 16% undersized graft model can significantly affect the force pattern applied to the local endothelial cell layer near the anastomosis by altering the local phase angle between the flow induced tangential force (synchronous with WSR) and the radial artery expansion induced cyclic hoop strain (synchronous with DV). This local phase angle is decreased by 65 degrees in the distal divergent geometry, while increased by 15 degrees in the proximal convergent geometry.

Arteries↗

PubMed2004

Computer simulation for prediction of performance and thermodynamic parameters of high energy materials.

A new code viz., Linear Output Thermodynamic User-friendly Software for Energetic Systems (LOTUSES) developed during this work predicts the theoretical performance parameters such as density, detonation factor, velocity of detonation, detonation pressure and thermodynamic properties such as heat of detonation, heat of explosion, volume of explosion gaseous products. The same code also assists in the prediction of possible explosive decomposition products after explosion and power index. The developed code has been validated by calculating the parameters of standard explosives such as TNT, PETN, RDX, and HMX. Theoretically predicated parameters are accurate to the order of +/-5% deviation. To the best of our knowledge, no such code is reported in literature which can predict a wide range of characteristics of known/unknown explosives with minimum input parameters. The code can be used to obtain thermochemical and performance parameters of high energy materials (HEMs) with reasonable accuracy. The code has been developed in Visual Basic having enhanced windows environment, and thereby advantages over the conventional codes, written in Fortran. The theoretically predicted HEMs performance can be directly printed as well as stored in text (.txt) or HTML (.htm) or Microsoft Word (.doc) or Adobe Acrobat (.pdf) format in the hard disk. The output can also be copied into the Random Access Memory as clipboard text which can be imported/pasted in other software as in the case of other codes.

Chemistry, Physical↗

PubMed2002

Computer simulations of slow progression of human immunodeficiency virus infection and relapse during anti-HIV treatment with reverse transcriptase inhibitors and protease inhibitors.

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been very serious problems since the 1980s. The progression of HIV infection into AIDS can be suppressed to some extent with reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs); however, there are some serious problems with treatments using the anti-HIV drugs (e.g. very high expense, complicated administration, and drug resistance). Hence, more studies on HIV and the development of more effective anti-HIV treatments are required. We consider it important to understand the complex dynamics involved in HIV infection, and we therefore propose new mathematical models of HIV infection. In the modeling, we have paid attention to the nonlinear relations between stimuli and responses (i.e., when responses are plotted against the logarithm of stimuli, a sigmoid curve is obtained), and to lymphoid organs which seem more important than the blood compartment (i.e., lymphoid organs are major reservoirs of HIV virions and contain most of the lymphocytes). Using the models, we have found that viral antigenic mutation plays an important role in the slow progression in the chronic phase of HIV infection. We have also found that viral antigenic mutation can cause relapse of HIV infection when the inhibition rate of anti-HIV drugs is low and that viral antigenic mutation cannot cause relapse when the inhibition rate is high.

Antigenic Variation↗

PubMedDate not supplied

Validation by computer simulation of two indirect methods for quantification of free water transport in peritoneal dialysis.

BACKGROUND: In peritoneal dialysis, approximately 40% of the total osmotic ultrafiltration (UF) induced by glucose can be predicted to be due to "free" water transport across aquaporin-1 (APQ-1). Theoretically, it would be possible to assess the fraction of free water transport in the early phase of a hypertonic dwell, when UF rate is high and the relative contribution of Na+ diffusion is low. La Milia et al. [La Milia V. et al. Fast-fast peritoneal equilibration test (FAST-FAST-PET): a simple method for peritoneal hydraulic permeability study [Abstract]. Nephrol Dial Transplant 2002; 17 (Suppl 1):17-18] suggested a technique to assess sodium-associated water transport based on sodium removal (Na+R) divided by the plasma Na+ concentration during a "fast-fast" (60 minute) peritoneal equilibration test (PET) for 3.86% glucose, yielding an estimate of the UF passing through the small pores (UFSP). Free water transport (UF through ultrasmall pores; UFUSP) was obtained by subtracting UFSP from total UF. Although peritoneal Na+ transport is almost totally convective, this technique will slightly overestimate small-pore UF due to the presence of some small-pore Na+ diffusion from the circulation during the dwell. A way of dealing with this problem was presented recently by Smit (Smit W. et al. Quantification of free water transport in peritoneal dialysis. Kidney Int 2004; 66:849-854). METHODS: In the present study we used the three-pore model of peritoneal transport to predict the degree of overestimation of UFSP for the technique presented by La Milia et al., and any potential deviations from theory for the technique presented by Smit et at. Simulations were performed under ordinary conditions and during simulated UF failure for 3.86% glucose. The fractional UF coefficient accounted for by APQ-1 was set at 2%. RESULTS: Estimating the UFSP from the sodium-associated water transport according to the method by La Milia et al. consistently overestimated UFSP and underestimated UFUSP. These errors were, however, minimal for dwells lasting between 30 and 80 minutes. The technique by Smit et al. to calculate aquaporin-mediated water flow (UFUSP), using an elaborate correction for Na+ diffusion from the circulation during the dwell, seemed accurate in most situations but, in general, tended to moderately overestimate UFUSP at early dwell times (<30 minutes) and underestimate UFUSP at long dwell times (4 hours). CONCLUSIONS: The technique presented by La Milia et at. to calculate free water transport during a fast-fast PET was found to be surprisingly accurate, although the procedure would further improve by the introduction of a correction algorithm. The technique by Smit is even more accurate for dwells up to 4 hours' duration. However, since the Smit technique is elaborate, it is less practical for routine determinations of aquaporin-mediated water transport in peritoneal dialysis.

Algorithms↗

PubMed2006

Computer simulation of the ionic atmosphere around Z-DNA.

We describe a coarse-grained model for Z-DNA that mimics the DNA shape with a relatively small number of repulsive interaction sites. In addition, negative charges are placed at the phosphate positions. The ionic atmosphere around this grooved Z-DNA model is then investigated with Monte Carlo simulation. Cylindrically averaged concentration profiles as well as the spatial distribution of ions have been calculated. The results are compared to those for other DNA models differing in the repulsive core. This allows the examination of the effect of the DNA shape in the ionic distribution. It is seen that the penetrability of the ions to the DNA groove plays an important role in the ionic distribution. The results are also compared with those reported for B-DNA. In both conformers the ions are structured in alternating layers of positive and negative charge. In Z-DNA the layers are more or less concentric to the molecular axis. Besides, no coions enter into the single groove of this conformer. On the contrary, the alternating layers of B-DNA are also structured along the axial coordinate with some coions penetrating into the major groove. In both cases we have found five preferred locations of the counterions and two for the coions. The concentration of counterions reaches its absolute maximum at the narrow Z-DNA groove and at the minor groove of B-DNA, the value of the maximum being higher in the Z conformer.

Computer Simulation↗

PubMed2006

A computer simulation analysis of the accuracy of partial genome sequencing and restriction fragment analysis in the reconstruction of phylogenetic relationships.

Partial genome sequencing (PGS) and restriction fragment analysis (RFA) are used frequently in molecular epidemiologic investigations. The relative accuracy of PGS and RFA in phylogenetic reconstruction has not been assessed. In this study, 32 model phylogenetic trees with 16 extant lineages were generated, for which DNA sequences were simulated under varying conditions of genome length, nucleotide substitution rate, and between-site substitution rate variation. Genotyping using PGS and RFA was simulated. The effect of tree structure (stemminess, imbalance, lineage variation) on the accuracy of phylogenetic reconstruction (topological and branch length similarity) was evaluated. Overall, PGS was more accurate than RFA. The accuracy of PGS increased with increasing sequence length. The accuracy of RFA increased with the number of restriction enzymes used. In fragment size comparison, the Dice and Nei-Li algorithms differed little, with both more accurate than the Fragment Size Distribution algorithm. For RFA, higher tree stemminess and longer genome length were associated with higher topological accuracy, whereas lower tree stemminess and lower substitution rates were associated with higher branch length accuracy. For PGS, lower tree imbalance was associated with higher topological accuracy, whereas lower tree stemminess, higher substitution rate, and lower between-site substitution rate variation were associated with higher branch length accuracy. RFA had higher topological accuracy than PGS only for the shortest sequence length (200 bps) at a low substitution rate, high tree stemminess, and long genome length. PGS had equal or higher accuracy in branch length reconstruction than RFA under all conditions investigated. Thus, partial genome sequencing is recommended over restriction fragment analysis for conditions within the parameter space examined.

Computational Biology↗

PubMed1996

Self-organization in computer simulated selective systems.

In certain biologic systems, the signal selects functional or numerical expansion of the recognizing elements. Examples of these systems include the immune system, brain cortex, and evolution. One common feature of these Darwinian-type systems is degenerate recognition, in which one signal can recognize several different elements, with different affinities and consequences. For example, T cell antigen receptors and antibodies demonstrate relative but not absolute specificity of recognition. Thus, the variables of dose of the signal and affinity of the recognizing element modulate the outcome. Another feature of these systems is the ability to create self-organized patterns, which do not mirror the incoming signals. The hypothesis of this study is that degenerate recognition with subsequent selection of recognizing elements can explain self-organization of these systems. An entirely numerical model was explored, using the cellular automata approach. Three intrinsic features of a common selective system were incorporated into this model: a large number of recognizing elements; degenerative recognition of stimuli by these elements; and subsequent selection. Different numerical patterns of incoming stimuli were tested. The model showed self-organizing dynamics. Usually, the population of recognizing elements demonstrated an initial period of equilibrium, then a chaotic transitional state, and, finally, the bifurcational appearance of a stable self-organized pattern. The final resolution into a stable pattern can be either gradual or quasi-saltational. I conclude that systems with a large number of recognizing elements, degenerative recognition, and selection of recognizing elements can self organize based upon the pattern of the incoming stimuli.

Computer Simulation↗

PubMed2004

Computer simulation of nickel in blood-plasma following the in vitro investigations of complex formation chemistry with polyamine(amide) ligands.

In- and out-of-cell potentiometric techniques have been used to determine the formation constants for nickel(II) with 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (L(1)), N,N[prime or minute]-bis(2-hydroxyiminopropionyl)propane-1,3-diamine (L(2)) and 1,15-bis(N,N-dimethyl)-5,11-dioxo-8-(N-benzyl)-1,4,8,12,15-pentaazapentadecane (L(3)) at 25 degrees C and an ionic strength of 0.15 mol dm(-3). Nickel(II) forms stable complexes with L(1) and L(2) where square-planar [NiLH(-1)] and [NiLH(-2)] species predominate under alkaline conditions. The square-planar coordination of nickel by L(1) has been confirmed by a single-crystal X-ray structure, UV/Vis spectrometry and molecular mechanics calculations of the [NiL(1)H(-1)] complex. The introduction of a third amine group into L(3) dramatically decreases the ligand's ability to complex Ni(II). This results from a change in structure of the complex which decreases the ability of the metal ion to promote the dissociation of the amide protons. Using a model of blood plasma, the high binding ability of L(1) towards Ni(II) is calculated to decrease the mobilisation of Cu(II) in plasma by approximately 65%. [CuL(1)H(-1)] is currently under investigation as an anti-inflammatory agent.

Computer Simulation↗

PubMed2002

Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations.

This article presents a molecular dynamics (MD) study of the cdk2 enzyme and its two complexes with the inhibitors isopentenyladenine and roscovitine using the Cornell et al. force field from the AMBER software package. The results show that inserting an inhibitor into the enzyme active site does not considerably change enzyme structure but it seemingly changes the distribution of internal motions. The inhibitor causes differences in the domain motions in free cdk2 and in its complexes. It was found out that repulsion of roscovitine N9 substituent causes conformational change on Lys 33 side chain. Isopentenyladenine forms with Lys 33 side chain terminal amino group a hydrogen bond. It implies that the cavity, where N9 substituent of roscovitine is buried, can adopt larger substituent due to Lys 33 side chain flexibility. The composition of electrostatic and van der Waals interactions between the inhibitor and the enzyme were also calculated along both cdk2/inhibitor MD trajectories together with MM-PB/GBSA analysis. These results show that isopentenyladenine-like inhibitors could be more effective after modifications leading to an increase in their van der Waals contact with the enzyme. We suggest that a way leading to better inhibitors occupying isopentenyladenine binding mode could be: to keep N9 and N7 purine positions free, to keep 3,3-dimethylallylamino group at C6 position, and to add, e.g., benzylamino group at C2 position. The results support the idea that the isopentenyladenine binding mode can be used for cdk2 inhibitors design and that all possibilities to improve this binding mode were not uncovered yet.

Adenine↗

PubMed1999

Computer simulation of flagellar movement: VII. Conventional but functionally different cross-bridge models for inner and outer arm dyneins can explain the effects of outer arm dynein removal.

Outer arm dynein removal from flagella by genetic or chemical methods causes decreased frequency and power, but little change in bending pattern. These results suggest that outer arm dynein operates within bends to increase the speed of bend propagation, but does not produce forces that alter the bending pattern established by inner arm dyneins. A flagellar model incorporating different cross-bridge models for inner and outer arm dyneins has been examined. The inner arm dynein model has a hyperbolic force-velocity curve, with a maximum average force at 0 sliding velocity of about 14 pN for each 96 nm group of inner arm dyneins. The outer arm dynein model has a very different force-velocity curve, with a maximum force at about 10-15% of V(max). The outer arm dynein model is adjusted so that the unloaded sliding velocity for a realistic mixture of inner and outer arm dyneins is twice the unloaded sliding velocity for the inner arm dynein model alone. With these cross-bridge models, a flagellar model can be obtained that reduces its sliding velocity and frequency by approximately 50% when outer arm dyneins are removed, with little change in bending pattern. The addition of outer arm dyneins, therefore, gives an approximately 4-fold increase in power output against viscous resistances, and outer arm dyneins may generate 90% or more of the power output. Cell Motil.

Animals↗

PubMed1991

Computer simulation of the steady-state input-output function of the cat medial gastrocnemius motoneuron pool.

1. A pool of 100 simulated motor units was constructed in which the steady-state neural and mechanical properties of the units were very closely matched to the available experimental data for the cat medial gastrocnemius motoneuron pool and muscle. The resulting neural network generated quantitative predictions of whole system input-output functions based on the single unit data. The results of the simulations were compared with experimental data on normal motor system behavior in humans and animals. 2. We considered only steady-state, isometric conditions. All motoneurons received equal proportions of the synaptic input, and no feedback loops were operative. Thus the intrinsic properties of the motor unit population alone determined the form of the system input-output function. Expressing the synaptic input in terms of effective synaptic current allowed the simulated motoneuron input-output functions to be specified by well-known firing rate-injected current relations. The motor unit forces were determined from standard motor unit force-frequency relations, and the system output at any input level was assumed to be the linear sum of the forces of the active motor units. 3. The steady-state input-output function of the simulated motoneuron pool had a roughly sigmoidal shape that was quite different from those derived from previous recruitment models, which did not incorporate frequency modulation. Frequency modulation in combination with the skewed distribution of thresholds (low values much more frequent than high) restricted upward curvature to low input levels, whereas frequency modulation alone was responsible for the final gradual approach to the maximum force output. 4. Sensitivity analyses were performed to assess the importance of several assumptions that were required to deal with gaps and uncertainties in the available experimental data. The shape of the input-output function was not critically dependent on any of these assumptions, including those specifying linear summation of inputs and outputs. 5. A key assumption of the model was that systematic variance in motor unit properties was much more important than random variance for determining the input-output function. Addition of random variance via Monte Carlo techniques showed that this assumption was correct. These results suggest that the output of a motoneuron pool should be quite tolerant of random variance in the distribution of synaptic inputs and yet substantially altered by any systematic differences, such as unequal distribution of inputs among different motor unit types.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed2001

Complex dynamics of adaptation in a nonaxenic microcystis culture. 2. Computer simulation of dinotrophenol effects.

A hypothesis was modeled to account for complex 20-day dynamics in a culture of blue-green algae Microcystis and heterotrophic bacteria exposed to 2,4-dinitrophenol (DNP). In trials with little or no added DNP, a limiting factor (light or CO(2)) may cause algal density to fluctuate after 14 days of increase. Such factors may be unimportant at levels of DNP that restrict photosynthesis. Bacterial growth may be limited by organic substrate, and bacteria may be more resistant to DNP than blue-green algae. Hence, at intermediate levels of DNP, substrate provided by increased algal death stimulates bacterial growth more than DNP retards it, causing a bacterial peak. Sorption of DNP to cells may cause the DNP decline. Greater growth and slower DNP decline in experiments with preexposed organisms indicate lower DNP sorption affinity in preexposed cells. Bacterial assimilation of DNP-containing substrate may cause the reappearance of DNP. The model reproduced the fluctuation in algal density after growth was limited and better growth and lower DNP decline with preexposed organisms. Reappearance of DNP occurred, but was not obvious. Bacterial dynamics were least well reproduced. Changes in bacterial constants most affected output. Despite model inadequacies, probable aspects of toxicant action in nature have been revealed. Ecological relationships among populations of different species and genetic differences among individuals may have led to lower than expected toxicity, adaptation, and even growth stimulation. Responses of single species tested in isolation may be inadequate to predict toxicant impact.

2,4-Dinitrophenol↗

PubMed2004

Computer-simulated phacoemulsification.

OBJECTIVE: To develop a simulator for training in phacoemulsification to be used as a learning device for both beginners and experienced surgeons to shorten the learning curve. DESIGN: Experimental study. METHODS: The system consists of a personal computer, a 3-dimensional visual interface, a phacoemulsification handpiece, and a nucleus manipulator and foot pedals for control of the phacoemulsification procedure and microscope adjustments. The simulation is based on generalized simulation software that can be also used for the development of other medical simulations. MAIN OUTCOME MEASURES: Qualitative statements given in a questionnaire. Medical students and ophthalmic surgeons with varying experience of phacoemulsification were tested. RESULTS: A simulator for training in phacoemulsification has been developed. The surgical procedures can be practiced any number of times, and there is no risk to patients. The efforts of the surgeon can be evaluated objectively. CONCLUSIONS: Studies have shown that the number of complications for an ophthalmic surgeon learning phacoemulsification decreases exponentially, reaching close to the asymptote only after several hundred procedures. Simulator training might shorten the learning period, reduce expensive supervision by an experienced surgeon, and maintain and improve the skills of experienced surgeons.

Computer Simulation↗

PubMed2005

Calculation of the hydration free energy difference between pyridine and its methyl-substituted derivatives by computer simulation methods.

The difference of the hydration free energy of pyridine and its methyl- and symmetrically dimethyl-substituted derivatives has been calculated by the method of free energy perturbation. To check the precision of the results obtained, we have repeated the calculations using thermodynamic integration over different paths. Besides the hydration free energy, the difference in the energy and entropy of hydration between pyridine and monomethyl- and dimethylpyridines has also been determined. The obtained results clearly show that the hydration free energy of the pyridine derivatives becomes more negative with each additional methyl group. However, the accuracy of the calculation does not allow us to draw any conclusion about the dependence of the hydration free energy on the location of the methyl group. The analysis of the Coulomb and Lennard-Jones contributions to the hydration free energy differences has shown the dominance of the latter term. The comparison of the hydration energy and free energy values has shown that there is a strong compensation effect between the energetic and entropic terms of the free energy. The hydration energy of the solute becomes considerably more negative with each additional methyl group due to the dispersion attraction between the methyl group and the surrounding water molecules. The introduction of a methyl group results in an approximately 30 J/(mol K) decrease of the entropy of hydration, and hence, at 300 K, the entropic contribution to the hydration free energy increases by about 9 kJ/mol. Due to their opposite signs, the entropic and energetic contributions largely cancel each other, resulting in approximately an order of magnitude smaller value for the free energy.

Computer Simulation↗