Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design

This is a brief review of the computational modeling of protein-ligand interactions using a recently developed fully polarizable continuum model (FPCM) and rational drug design. Computational modeling has become a powerful tool in understanding detailed protein-ligand interactions at molecular level and in rational drug design. To study the binding of a protein with multiple molecular species of a ligand, one must accurately determine both the relative free energies of all of the molecular species in solution and the corresponding microscopic binding free energies for all of the molecular species binding with the protein. In this paper, we aim to provide a brief overview of the recent development in computational modeling of the solvent effects on the detailed protein-ligand interactions involving multiple molecular species of a ligand related to rational drug design. In particular, we first briefly discuss the main challenges in computational modeling of the detailed protein-ligand interactions involving the multiple molecular species and then focus on the FPCM model and its applications. The FPCM method allows accurate determination of the solvent effects in the first-principles quantum mechanism (QM) calculations on molecules in solution. The combined use of the FPCM-based QM calculations and other computational modeling and simulations enables us to accurately account for a protein binding with multiple molecular species of a ligand in solution. Based on the computational modeling of the detailed protein-ligand interactions, possible new drugs may be designed rationally as either small-molecule ligands of the protein or engineered proteins that bind/metabolize the ligand. The computational drug design has successfully led to discovery and development of promising drugs.     

Free Energy Calculations for DNA Near Surfaces Using an Ellipsoidal Geometry

The change in some thermodynamic quantities such as Gibbs' free energy, entropy and enthalpy of the binding of two DNA strands (forming a double helix), while one is tethered to a surface and are analytically calculated. These particles are submerged in an electrolytic solution; the ionic strength of the media allows the linearized version of the Poisson-Boltzmann equation (from the theory of the double layer interaction) to properly describe the interactions [13]. There is experimental and computational evidence that an ion penetrable ellipsoid is an adequate model for the single strand and the double helix [22–25]. The analytic solution provides simple calculations useful for DNA chip design. The predicted electrostatic effects suggest the feasibility of electronic control and detection of DNA hybridization in the fast growing area of DNA recognition.     

Investigation of implicit memory during isoflurane anesthesia for elective surgery using the process dissociation procedure

BACKGROUND: This prospective study evaluated memory function during general anesthesia for elective surgery and its relation to depth of hypnotic state. The authors also compared memory function in anesthetized and nonanesthetized subjects. METHODS: Words were played for 70 min via headphones to 48 patients (aged 18-70 yr) after induction of general anesthesia for elective surgery. Patients were unpremedicated, and the anesthetic regimen was free. The Bispectral Index (BIS) was recorded throughout the study. Within 36 h after the word presentation, memory was assessed using an auditory word stem completion test with inclusion and exclusion instructions. Memory performance and the contribution of explicit and implicit memory were calculated using the process dissociation procedure. The authors applied the same memory task to a control group of nonanesthetized subjects. RESULTS: Forty-seven patients received isoflurane, and one patient received propofol for anesthesia. The mean (+/- SD) BIS was 49 +/- 9. There was evidence of memory for words presented during light (BIS 61-80) and adequate anesthesia (BIS 41-60) but not during deep anesthesia (BIS 21-40). The process dissociation procedure showed a significant implicit memory contribution but not reliable explicit memory contribution (mean explicit memory scores 0.05 +/- 0.14, 0.04 +/- 0.09, and 0.05 +/- 0.14; mean automatic influence scores 0.14 +/- 0.12, 0.17 +/- 0.17, and 0.18 +/- 0.21 at BIS 21-40, 41-60, and 61-80, respectively). Compared with anesthetized patients, the memory performance of nonanesthetized subjects was better, with a higher contribution by explicit memory and a comparable contribution by implicit memory. CONCLUSION: During general anesthesia for elective surgery, implicit memory persists even in adequate hypnotic states, to a comparable degree as in nonanesthetized subjects.     

Investigation of Implicit Memory during Isoflurane Anesthesia for Elective Surgery Using the Process Dissociation Procedure

Background: This prospective study evaluated memory function during general anesthesia for elective surgery and its relation to depth of hypnotic state. The authors also compared memory function in anesthetized and nonanesthetized subjects.

Methods: Words were played for 70 min via headphones to 48 patients (aged 18-70 yr) after induction of general anesthesia for elective surgery. Patients were unpremedicated, and the anesthetic regimen was free. The Bispectral Index (BIS) was recorded throughout the study. Within 36 h after the word presentation, memory was assessed using an auditory word stem completion test with inclusion and exclusion instructions. Memory performance and the contribution of explicit and implicit memory were calculated using the process dissociation procedure. The authors applied the same memory task to a control group of nonanesthetized subjects.

Results: Forty-seven patients received isoflurane, and one patient received propofol for anesthesia. The mean (+/- SD) BIS was 49 +/- 9. There was evidence of memory for words presented during light (BIS 61-80) and adequate anesthesia (BIS 41-60) but not during deep anesthesia (BIS 21-40). The process dissociation procedure showed a significant implicit memory contribution but not reliable explicit memory contribution (mean explicit memory scores 0.05 +/- 0.14, 0.04 +/- 0.09, and 0.05 +/- 0.14; mean automatic influence scores 0.14 +/- 0.12, 0.17 +/- 0.17, and 0.18 +/- 0.21 at BIS 21-40, 41-60, and 61-80, respectively). Compared with anesthetized patients, the memory performance of nonanesthetized subjects was better, with a higher contribution by explicit memory and a comparable contribution by implicit memory.     

Effect of the Reaction Field on Molecular Forces and Torques Revealed by an Image-Charge Solvation Model

We recently developed the Image-Charge Solvation Model (ICSM), which is an explicit/implicit hybrid model to accurately account for long-range electrostatic forces in molecular dynamics simulations [Linet al., J. Chem. Phys., 131, 154103, 2009]. The ICSM has a productive spherical volume within the simulation cell for which key physical properties of bulk water are reproduced, such as density, radial distribution function, diffusion constants and dielectric properties. Although the reaction field (RF) is essential, it typically accounts for less than 2% of the total electrostatic force on a water molecule. This observation motivates investigating further the role of the RF within the ICSM. In this report we focus on distributions of forces and torques on water molecules as a function of distance from the origin and make extensive tests over a range of model parameters where Coulomb forces are decomposed into direct interactions from waters modeled explicitly and the RF. Molecular torques due to the RF typically account for 20% of the total torque, revealing why the RF plays an important role in the dielectric properties of simulated water. Moreover, it becomes clear that the buffer layer in the ICSM is essential to mitigate artifacts caused by the discontinuous change in dielectric constants at the explicit/implicit interface.     

Image Charge Methods for a Three-Dielectric-Layer Hybrid Solvation Model of Biomolecules

This paper introduces a three dielectric layer hybrid solvation model for treating electrostatic interactions of biomolecules in solvents using the Poisson-Boltzmann equation. In this model, an interior spherical cavity will contain the solute and some explicit solvent molecules, and an intermediate buffer layer and an exterior layer contain the bulk solvent. A special dielectric permittivity profile is used to achieve a continuous dielectric transition from the interior cavity to the exterior layer. The selection of this special profile using a harmonic interpolation allows an analytical solution of the model by generalizing the classical Kirkwood series expansion. Discrete image charges are used to speed up calculations for the electrostatic potential within the interior and buffer layer regions. Semi-analytical and least squares methods are used to construct an accurate discrete image approximation for the reaction field due to solvent with or without salt effects. In particular, the image charges obtained by the least squares method provide accurate approximations to the reaction field independent of the ionic concentration of the solvent. Numerical results are presented to validate the accuracy and effectiveness of the image charge methods.     

Decentralized minimum-energy control and coordination of large scale linear systems

A two-level hierarchical algorithm of the interaction prediction type is derived for the decentralized optimal control of linear systems with fixed terminal state, linear interactions, and a minimum energy criterion. The algorithm is noniterative at the infimal level and utilizes successive approximation with averaging for the coordination. Numerical experiments compare the effect of the interactions, sampling times, and time horizon on the convergence of the algorithm.     

GABA alpha6 receptors mediate midazolam-induced anxiolysis

STUDY OBJECTIVE: To compare the ability of midazolam to produce sedation and anxiolysis and attenuate memory in 100 patients aged 20 to 70 years. The effect of a point mutation (Pro385Ser) for the gamma amino-butyric acid (GABA) alpha6 receptor on the sedative, anxiolytic, and memory effects of midazolam was determined. SETTING: University hospital. DESIGN: Prospective, randomized, double-blind study. PATIENTS: 100 ASA physical status I and II patients scheduled for surgery. INTERVENTIONS: Two midazolam dose groups, 20 microg/kg and 40 microg/kg, with 40 patients per group and 20 control patients receiving saline as a sham control. Treatments were randomly assigned. Blood was collected at the beginning of each study. MEASUREMENTS: Patient sedation and anxiolysis were measured using a visual analog scale and explicit and implicit memory of a word task determined before and six minutes after midazolam or saline. A 365-base pair fragment of the GABA alpha6 receptor gene was amplified by polymerase chain reaction (PCR) from patient blood DNA and digested with the restrictase Fok I. Restriction fragments were visualized by ethidium bromide staining after electrophoresis to evaluate the GABA alpha6 receptor subunit mutation. MAIN RESULTS: Midazolam produced dose-related sedation and anxiolysis. Explicit (recall) memory was attenuated with high-dose midazolam but implicit (recognition) memory remained intact. The GABA alpha6 receptor mutation did not affect baseline sedation, anxiety, or memory but significantly attenuated the anxiolytic effect of low-dose midazolam. Sedation and explicit memory were not affected by the mutation. CONCLUSIONS: A Pro385Ser mutation of the GABA alpha6 receptor subunit decreased the anxiolytic effect of low-dose midazolam.     

A Generalized Peierls-Nabarro Model for Curved Dislocations Using Discrete Fourier Transform

In this paper, we present a generalized Peierls-Nabarro model for curved dislocations using the discrete Fourier transform. In our model, the total energy is expressed in terms of the disregistry at the discrete lattice sites on the slip plane, and the elastic energy is obtained efficiently within the continuum framework using the discrete Fourier transform. Our model directly incorporates into the total energy both the Peierls energy for the motion of straight dislocations and the second Peierls energy for kink migration. The discreteness in both the elastic energy and the misfit energy, the full long-range elastic interaction for curved dislocations, and the changes of core and kink profiles with respect to the location of the dislocation or the kink are all included in our model. The model is presented for crystals with simple cubic lattice. Simulation results on the dislocation structure, Peierls energies and Peierls stresses of both straight and kinked dislocations are reported. These results qualitatively agree with those from experiments and atomistic simulations.     

Computer Simulation of Helium Effects in Plutonium During the Aging Process of Self-Radiation Damage

Due to α radioactive decay Pu is vulnerable to aging. The behavior of He in Pu is the foundation for understanding Pu self-radiation damage aging. Molecular dynamics technique is performed to investigate the behavior of defects, the interaction between He and defects, the processes of initial nucleation and growth of He bubble and the dependence of He bubble on the macroscopical properties of Pu. Modified embedded atom method, Morse pair potential and the Lennard-Jones pair potential are used for describing the interactions of Pu-Pu, Pu-He and He-He, respectively. The main calculated results show that He atoms can combine with vacancies to form He-vacancy cluster (i.e., the precursor of He bubble) during the process of self-radiation as a result of high binding energy of an interstitial He atom to vacancy; He bubble's growth can be dominated by the mechanism of punching out of dislocation loop; the swelling induced by He bubble is very small; grain boundaries give rise to an energetically more favorable zone for the interstitial He atom and self-interstitial atom accumulation than for vacancy accumulation; the process of He release can be identified as the formation of release channel induced by the cracking of He bubble and surface structure.     

Structure of human sperm chromatin: a study on the accessibility of DNA to macromolecules

The structure of human sperm chromatin compared with somatic chromatin (liver) was studied by titration of the exposed DNA-phosphate groups with poly-1-lysine (3000 and 28,100 MW) and by their susceptibility to the hydrolytic action of micrococcal nuclease and DNase I. With both sizes of polylysine used, the binding values were significantly lower for sperm chromatin (0.31 +/- 0.05) than for liver chromatin (0.52 +/- 0.05), indicating the presence of about 30% and 52% of free phosphate groups, respectively. Interaction with liver chromatin left no polylysine molecules partially unbound ("wastage") even when 28,100 MW polylysine was used; on the contrary, sperm chromatin showed 26% of "wasted" polylysine even when the smaller polymer was used, indicating that in sperm chromatin the accessible DNA zones are usually no longer than 42 A, that is, 12 base pair. Sperm chromatin was notably more susceptible to both micrococcal nuclease and DNase I action than liver chromatin. However, in the presence of saturating concentrations of polylysine they were similarly protected. Micrococcal nuclease and DNase I hydrolysis products of sperm fractions when submitted to electrophoresis produced a polydisperse smearing pattern along the gel that was difficult to correlate with the presence of nucleosomal structure.     

Lymphocyte costimulatory receptors in renal disease and transplantation

Cell-to-cell signal exchange during antigen presentation deeply influences the profile and extent of the immune response. Together with the TCR/MHC-mediated signal, accessory signals are provided to the T cell by the antigen-presenting cell (APC), through specific receptor-ligand interactions that represent indispensable costimulation for T-cell activation and survival. The main costimulatory pathways are the B7 family members and the CD40-CD154 receptor-ligand pair. B7-1 and B7-2 costimulate T-cells by binding to CD28. Their binding is prevented by the neoexpression of CTLA4, a CD28 homologue that can deliver a negative signal. Another CD28-like molecule, called ICOS (inducible costimulator), has been described and binds B7RP-1, a third member of the B7 family, but not B7-1 and B7-2. The CD40-CD154 interaction works as a two way costimulatory system by triggering activation signals to both T-cell and APCs. Its importance is highlighted by the discovery that mutations of the CD154 gene are responsible for a severe human immunodeficiency. Disruption of the natural costimulatory interaction was highly effective for prevention and treatment in several experimental models of autoimmune disease and transplant rejection. This review focuses on the most significant advances in understanding the physiopathological events involving costimulatory molecules, and their impact on renal diseases and transplantation.     

Quantifying the contributions of structure to annulus fibrosus mechanical function using a nonlinear, anisotropic, hyperelastic model.

The annulus fibrosus of the intervertebral disc is comprised of concentric lamella of oriented collagen fibers embedded in a hydrated proteoglycan matrix with smaller amounts of minor collagens, elastin, and small proteoglycans. Its structure and composition enable the disc to withstand complex loads and result in inhomogeneous, anisotropic, and nonlinear mechanical behaviors. The specific contributions of the annulus fibrosus constituent structures to mechanical function remain unclear. Therefore, the objective of this study was to use a structurally motivated, anisotropic, nonlinear strain energy model of annulus fibrosus to determine the relative contributions of its structural components to tissue mechanical behavior. A nonlinear, orthotropic hyperelastic model was developed for the annulus fibrosus. Terms to describe fibers, matrix, and interactions between annulus fibrosus structures (shear and normal to the fiber directions) were explicitly included. The contributions of these structures were analyzed by including or removing terms and determining the effect on the fit to multidimensional experimental data. Correlation between experimental and model-predicted stress, a Bland-Altman analysis of bias and standard deviation of residuals, and the contribution of structural terms to overall tissue stress were calculated. Both shear and normal interaction terms were necessary to accurately model multidimensional behavior. Inclusion of shear interactions more accurately described annulus fibrosus nonlinearity. Fiber stretch and shear interactions dominated contributions to circumferential direction stress, while normal and shear interactions dominated axial stress. The results suggest that interactions between fibers and matrix, perhaps facilitated by crosslinks, elastin, or minor collagens, augment traditional (i.e., fiber-uncrimping) models of nonlinearity.     

Structure-function relationships in aquaporins

The identification of members of the aquaporin family as the primary water channels of cell membranes has been followed up by an intense effort to determine how these channels work. Specifically, investigators have sought to learn why these channels are selective for water and how they exclude proton trafficking. Molecular-dynamics studies using elegant, extremely detailed computer models based on accurate crystallographic maps of the channels show the basis for the selectivity of the channel. Channel size, the location of hydrophobic amino-acid side chains, and specific interactions of water dipoles with a charged residue near the most constricted point of the channel indicate that water molecules travel in single file through the center of the channel, and that the orientation of water molecules is manipulated to prevent the formation of a water wire spanning the channel. Finally, the number of water molecules calculated to be aligned in single file in the channel constriction fits predictions based on classic studies of the osmotic permeability: diffusive permeability ratios in water-permeable membranes.     

The interactions of ‘non-aggregating’ proteoglycans

The small proteoglycans decorin, biglycan and fibromodulin were prepared as a mixture from bovine nasal cartilage. The proteoglycans in this mixture were shown to interact with hyaluronate immobilized on Sepharose beads under isotonic conditions. The interaction could be disrupted by increasing the ionic strength of the solvent by enhancing the concentration of NaCl. To further characterize the proteoglycans of this mixture, they were visualized with the glycerol spraying/rotary shadowing technique for electron microscopy. They were shown to have a globular core protein and one or more glycosaminoglycan chains. The molecules, moreover, were organized as multimeric complexes, and their association one with another appeared to be mediated by either core protein or glycosaminoglycan chain interactions. Complexes were shown by rotary shadowing microscopy to associate with hyaluronate in solution. The combined results of this study show that as a mixture, the small proteoglycans of cartilage can interact with hyaluronate, though not necessarily as discrete monomers but rather as multimeric complexes. The observations made in this study also suggest that a similar interaction could occur in vivo, where the interaction between small proteoglycans and hyaluronate may have a functional significance in the maintenance of cartilage homeostasis.     

Opioid-volatile anesthetic synergy: a response surface model with remifentanil and sevoflurane as prototypes

BACKGROUND: Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane. METHODS: Sixteen adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the Observer's Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observer's Assessment of Alertness/Sedation score > or = 4) for anesthetics lasting 30-900 min. RESULTS: Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil. CONCLUSION: Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.