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Robert A Latour

Publications and source records attributed to Robert A Latour.

14 recordsLinked to original sources
PubMed2006

Thermodynamic perspectives on the molecular mechanisms providing protein adsorption resistance that include protein-surface interactions.

Current theories regarding the molecular mechanisms that provide protein adsorption resistance primarily focus on the characteristics of various types of surface-tethered chains and their interactions with water but often neglect their interactions with the protein. Such theories thus do not provide a complete explanation for protein adsorption resistance. The real issue that must be addressed is which properties enable surfaces to interact with water more favorably than with proteins. To address this issue, a thermodynamic treatment of protein adsorption to surface-tethered chains is presented and specific molecular-level interactions are addressed that contribute to enthalpy, entropy, and free energy changes that are involved during protein adsorption processes. Based on this analysis, it is proposed that two independently controllable sets of criteria provide conditions that are thermodynamically favorable for protein adsorption resistance: (1) well-hydrated long flexible surface-tethered chains with packing density sufficiently low to allow chain mobility while still providing complete surface coverage, and (2) surface-tethered chains that contain hydrogen-bondable groups that are readily accessible to water molecules but not to the hydrogen bond-forming groups of a protein.

Adsorption↗
PubMed2006

Comparison of implicit solvent models for the simulation of protein-surface interactions.

Empirical force field-based molecular simulations can provide valuable atomistic-level insights into protein-surface interactions in aqueous solution. While the implicit treatment of solvation effects is desired as a means of improving simulation efficiency, existing implicit solvent models were primarily developed for the simulation of peptide or protein behavior in solution alone, and thus may not be appropriate for protein interactions with synthetic material surfaces. The objective of this research was to calculate the change in free energy as a function of surface-separation distance for peptide-surface interactions using different empirical force field-based implicit solvation models (ACE, ASP, EEF1, and RDIE with the CHARMM 19 force field), and to compare these results with the same calculations conducted using density functional theory (DFT) combined with the self-consistent reaction field (SCRF) implicit solvation model. These comparisons show that distinctly different types of behavior are predicted with each implicit solvation method, with ACE providing the best overall agreement with DFT/SCRF calculations. These results also identify areas where ACE is in need of improvement for this application and provide a basis for subsequent parameter refinement.

Computer Simulation↗
PubMed2005

Prediction of the orientations of adsorbed protein using an empirical energy function with implicit solvation.

When simulating protein adsorption behavior, decisions must first be made regarding how the protein should be oriented on the surface. To address this problem, we have developed a molecular simulation program that combines an empirical adsorption free energy function with an efficient configurational search method to calculate orientation-dependent adsorption free energies between proteins and functionalized surfaces. The configuration space is searched systematically using a quaternion rotation technique, and the adsorption free energy is evaluated using an empirical energy function with an efficient grid-based calculational method. In this paper, the developed method is applied to analyze the preferred orientations of a model protein, lysozyme, on various functionalized alkanethiol self-assembled monolayer (SAM) surfaces by the generation of contour graphs that relate adsorption free energy to adsorbed orientation, and the results are compared with experimental observations. As anticipated, the adsorbed orientation of lysozyme is predicted to be dependent on the discrete organization of the functional groups presented by the surface. Lysozyme, which is a positively charged protein, is predicted to adsorb on its 'side' on both hydrophobic and negatively charged surfaces. On surfaces with discrete positively charged sites, attractive interaction energies can also be obtained due to the presence of discrete local negative charges present on the lysozyme surface. In this case, 'end-on' orientations are preferred. Additionally, SAM surface models with mixed functionality suggest that the interactions between lysozyme and surfaces could be greatly enhanced if individual surface functional groups are able to access the catalytic cleft region of lysozyme, similar to ligand-receptor interactions. The contour graphs generated by this method can be used to identify low-energy orientations that can then be used as starting points for further simulations to investigate conformational changes induced in protein structure following initial adsorption.

Adsorption↗
PubMed2005

Direct correlation between adsorption-induced changes in protein structure and platelet adhesion.

It is widely recognized that adsorbed proteins on biomaterial surfaces tend to initiate thrombus formation, although the specific mechanisms involved are still not well understood. In attempts to decrease the conformational change of adsorbed proteins, surface treatments that reduce surface hydrophobicity have been considered, such as the sulfonation of low-density polyethylene and isotactic polypropylene. The objectives of this present research were to study how changes in surface chemistry influence the degree of conformational change of adsorbing proteins and to investigate the correlation between the change in adsorbed protein structure and platelet response. Adsorbed porcine serum albumin and porcine fibrinogen were used as the model proteins for determining the effects of sulfonation on protein conformational change. Circular dichroism spectroscopy studies showed that the proteins were less altered structurally on the sulfonated surfaces. Platelet adhesion studies were used to correlate the number of adhered platelets with the amount of conformational change in adsorbed proteins on the polymer surface. The results of these studies show a linear correlation between platelet adhesion and the degree of adsorption-induced protein conformational change. These findings suggest that the degree of protein conformational change after adsorption is a dominant mechanism governing platelet interactions with biomaterial surfaces.

Adsorption↗
PubMed2005

Molecular dynamics simulations of peptide-surface interactions.

Proteins, which are bioactive molecules, adsorb on implants placed in the body through complex and poorly understood mechanisms and directly influence biocompatibility. Molecular dynamics modeling using empirical force fields provides one of the most direct methods of theoretically analyzing the behavior of complex molecular systems and is well-suited for the simulation of protein adsorption behavior. To accurately simulate protein adsorption behavior, a force field must correctly represent the thermodynamic driving forces that govern peptide residue-surface interactions. However, since existing force fields were developed without specific consideration of protein-surface interactions, they may not accurately represent this type of molecular behavior. To address this concern, we developed a host-guest peptide adsorption model in the form of a G(4)-X-G(4) peptide (G is glycine, X is a variable residue) to enable determination of the contributions to adsorption free energy of different X residues when adsorbed to functionalized Au-alkanethiol self-assembled monolayers (SAMs). We have previously reported experimental results using surface plasmon resonance (SPR) spectroscopy to measure the free energy of peptide adsorption for this peptide model with X = G and K (lysine) on OH and COOH functionalized SAMs. The objectives of the present research were the development and assessment of methods to calculate adsorption free energy using molecular dynamics simulations with the GROMACS force field for these same peptide adsorption systems, with an oligoethylene oxide (OEG) functionalized SAM surface also being considered. By comparing simulation results to the experimental results, the accuracy of the selected force field to represent the behavior of these molecular systems can be evaluated. From our simulations, the G(4)-G-G(4) and G(4)-K-G(4) peptides showed minimal to no adsorption to the OH SAM surfaces and the G(4)-K-G(4) showed strong adsorption to the COOH SAM surface, which is in agreement with our SPR experiments. Contrary to our experimental results, however, the simulations predicted a relatively strong adsorption of G(4)-G-G(4) peptide to the COOH SAM surface. In addition, both peptides were unexpectedly predicted to adsorb to the OEG surface. These findings demonstrate the need for GROMACS force field parameters to be rebalanced for the simulation of peptide adsorption behavior on SAM surfaces. The developed methods provide a direct means of assessing, modifying, and validating force field performance for the simulation of peptide and protein adsorption to surfaces, without which little confidence can be placed in the simulation results that are generated with these types of systems.

Adsorption↗
PubMed2005

Molecular simulation to characterize the adsorption behavior of a fibrinogen gamma-chain fragment.

Implants invoke inflammatory responses from the body even if they are chemically inert and nontoxic. It has been shown that a crucial precedent event in the inflammatory process is the spontaneous adsorption of fibrinogen (Fg) on implant surfaces, which is typically followed by the presence of phagocytic cells. Interactions between the phagocyte integrin Mac-1 and two short sequences within the fibrinogen gamma chain, gamma190-202 and gamma377-395, may partially explain phagocyte accumulation at implant surfaces. These two sequences are believed to form an integrin binding site that is inaccessible when Fg is in its soluble-state structure but then becomes available for Mac-1 binding following adsorption, presumably due to adsorption-induced conformational changes. The objective of this research was to theoretically investigate this possibility by using molecular dynamics simulations of the gamma-chain fragment of Fg over self-assembled monolayer (SAM) surfaces presenting different types of surface chemistry. The GROMACS software package was used to carry out the molecular simulations in an explicit solvation environment over a 5 ns period of time. The adsorption of the gamma-chain of fibrinogen was simulated on five types of SAM surfaces. The simulations showed that this protein fragment exhibits distinctly different adsorption behavior on the different surface chemistries. Although the trajectory files showed that significant conformational changes did not occur in this protein fragment over the time frame of the simulations, it was predicted that the protein does undergo substantial rotational and translational motions over the surface prior to stabilizing in various preferred orientations. This suggests that the kinetics of surface-induced conformational changes in a protein's structure might be much slower than the kinetics of orientational changes, thus enabling the principles of adsorption thermodynamics to be used to guide adsorbing proteins into defined orientations on surfaces before large conformational changes can occur. This finding may be very important for biomaterial surface design as it suggests that surface chemistry can potentially be used to directly control the orientation of adsorbing proteins in a manner that either presents or hides specific bioactive sites contained within a protein's structure, thereby providing a mechanism to control cellular responses to the adsorbed protein layer.

Adsorption↗
PubMed2005

Visualizing adhesion-induced agglutination of Escherichia coli with mannosylated nanoparticles.

Polymeric nanoparticles covalently functionalized with derivatized D-mannose molecules were synthesized and characterized. These nanoparticles have an average size of approximately 160 nm in diameter, thus bearing a large number of surface-tethered mannose moieties for multivalent interactions with adhesins on bacterial cells. Specifically, the mannosylated nanoparticles bind strongly with Escherichia coli, allowing the convenient visualization of adhesion interactions under a conventional electron microscope. Since a single nanoparticle is capable of binding more than one cell, the adhesion interactions result in significant nanoparticle-mediated cell agglutination according to electron microscopy imaging. Potential applications of the mannosylated nanoparticles in the inhibition of enteropathogenic infections are discussed.

Adhesins, Escherichia coli↗
PubMed2004

A molecular modeling study of the effect of surface chemistry on the adsorption of a fibronectin fragment spanning the 7-10th type III repeats.

Although it is well documented that proteins adsorb onto biomaterial surfaces, relatively little is quantitatively understood about the effects of adsorption on protein orientation and conformation. Because this is the primary determining factor of protein bioactivity, the ability to accurately predict a protein's orientation and conformation following adsorption will be essential for the rational design of biomaterial surfaces to control biological responses. Force field-based computational chemistry methods provide an excellent means to theoretically address this issue, with the nontrivial requirement that the force field must be tailored to appropriately represent protein adsorption behavior. Accordingly, we have modified an existing force field (CHARMm) based on semiempirical quantum-mechanical peptide adsorption data to enable it to simulate protein adsorption behavior in an implicit aqueous environment. This modified force field was then applied to predict the adsorption behavior of the 7-10 type III repeats of fibronectin on functionalized surfaces. Predicted changes in adsorption energy and adsorption-induced conformation as a function of surface chemistry were found to correlate well with experimentally observed trends for these same systems. This work represents a first attempt towards the development of a molecular mechanics force field that is specifically parameterized to accurately simulate protein adsorption to biomaterial surfaces.

Coated Materials, Biocompatible↗
PubMed2003

Theoretical analysis of adsorption thermodynamics for charged peptide residues on SAM surfaces of varying functionality.

Cellular response to an implant is largely controlled by protein adsorption because cells directly interact with the adsorbed protein rather than the implant surface. Protein adsorption will occur when the change in Gibbs free energy (Delta G) of the system decreases during the adsorption process. Electrostatic interactions between charged peptide residues presented by a protein's surface and surface functional groups greatly contribute to the Delta G of protein adsorption. In this study, semiempirical molecular orbital calculations were used to theoretically determine the adsorption enthalpy between charged peptide residues [aspartic acid (-1), glutamic acid (-1), and arginine (+1)] and functionalized SAM surfaces [methyl, hydroxyl, amine (+1), and carboxylic acid (-1)]. Additional enthalpic and entropic contributions attributed to water restructuring effects were then approximated based on literature values for functional group solvation and considered along with the calculated enthalpy values to estimate the change in Delta G for each residue/surface system as a function of surface separation distance. The results predict long-range attraction and repulsion to the opposite and same-charge residue/surface systems, respectively, followed by strong short-range repulsion caused by functional group dehydration. Short-range repulsion alone was predicted for the charged residues on the methyl and hydroxyl surfaces. These results provide a theoretical quantitative description of fundamental mechanisms governing protein adsorption behavior and provide a basis for the development of a knowledge-based surface design approach to control biological response.

Adsorption↗
PubMed2002

Theoretical analysis of adsorption thermodynamics for hydrophobic peptide residues on SAM surfaces of varying functionality.

At a fundamental level, protein adsorption to a synthetic surface must be strongly influenced by the interaction between the peptide residues presented by the protein's surface (primary protein structure) and the functional groups presented by the synthetic surface. In this study, semi-empirical molecular modeling was used along with experimental wetting data to theoretically approach protein adsorption at this primary structural level. Changes in enthalpy, entropy, and Gibbs free energy were calculated as a function of residue-surface separation distance for the adsorption of individual hydrophobic peptide residues (valine, leucine, phenylalanine) on alkanethiol self-assembled monolayers on gold [Au-S(CH(2))(15)-X; X = CH(3), OH, NH(3)(+), COO(-)]. The results predict that the adsorption of each type of hydrophobic residue is energetically favorable and entropy dominated on a methyl-terminated hydrophobic surface, energetically unfavorable and enthalpy dominated on a hydroxyl-terminated neutral hydrophilic surface, and very slightly favorable to unfavorable and enthalpy dominated on charged surfaces. These theoretical results provide a basis for understanding some of the fundamental effects governing protein adsorption to synthetic surfaces. This level of understanding is needed for the proactive design of surfaces to control protein adsorption and subsequent cellular response for both implant and tissue engineering applications.

Adsorption↗
PubMed2002

Progressive failure analysis of laminated composite femoral prostheses for total hip arthroplasty.

In this research program, a numerical method was developed to predict the progressive failure of a thick laminated composite femoral component for total hip arthroplasty. A 3-D global/local technique was used to capture the overall structural response of this system while also enabling the 3-D ply level stress state to be determined efficiently and accurately. Different failure criteria and different material degradation models were incorporated as individual subroutines in the numerical method, giving it the flexibility to model a wide range of materials and structures. Numerical modeling was also conducted to design experimental test methods for component fatigue testing that closely simulate in vivo loading conditions. Parametric studies were then conducted with the numerical model of the experimental system and the results were compared to the actual experimentally determined damage behavior of fabricated laminated composite femoral component to assess which parameter set most accurately predicted the actual damage development behavior. The best fitting parameter set was then applied to the failure problem of the composite hip prosthesis implanted in an anatomically modeled femur to predict in vivo performance. This work provides a ply level understanding of the damage behavior of laminated composite femoral components and a numerical tool which can serve as a guide for the design of fatigue resistant implants made from composite material for this and other implant applications.

Arthroplasty, Replacement, Hip↗
PubMed2002

A theoretical analysis of the thermodynamic contributions for the adsorption of individual protein residues on functionalized surfaces.

Although the denaturing of adsorbed proteins on biomaterials surfaces is believed to lead to adverse tissue reactions to implanted materials, very little is currently known of the actual mechanisms involved. These mechanisms must be understood if surfaces are to be proactively designed to control protein adsorption behavior. Concepts widely employed in rational drug design and in protein and RNA folding predictions provide a means to approach this problem. Accordingly, a theoretical analysis has been conducted to estimate the thermodynamic contributions (changes in enthalpy, entropy, and Gibbs free energy) for the adsorption of selected individual mid-chain protein residues to functionalized surfaces. Enthalpic contributions from residue-surface interactions were calculated using semi-empirical quantum mechanical-based computational chemistry methods in a simulated aqueous environment (MOPAC/COSMO), and enthalpic and entropic contributions due to water restructuring effects assumed to occur during adsorption were estimated from experimental data for functional group wetting and calculated changes in solvent accessible surface area as each protein residue approached each surface. When combined with intraprotein residue-residue interactions, the understanding of residue-surface adsorption energy relationships provides a means to begin to predict protein adsorption behavior as a function of biomaterials surface chemistry. It is recognized that several assumptions have been made in this approach that could be challenged, and that truncations necessary due to programming limitations have been applied that may neglect potentially important interactions. Therefore, it must be understood that the modeling predictions may not be directly applicable to biomaterials for surface design under actual physiologic conditions at this stage. However, this attempt at modeling fundamental components of protein adsorption is presented as an initial approach to understanding these complex events.

Adsorption↗
PubMedDate not supplied

Failure analysis of composite femoral components for hip arthroplasty.

In this research, a numerical method was developed for predicting the progressive failure of thick laminated composite femoral components. A three-dimensional (3-D) global/ 3-D local technique was developed to capture the overall structural response of this system, while also enabling the 3-D ply-level stress state to be determined efficiently and accurately. Different failure criteria and material degradation models were incorporated in the method, giving it the flexibility to model a wide range of materials and structures. Numerical modeling was also conducted to design experimental test methods to simulate in vivo loading conditions for component fatigue tests. Parametric studies were then conducted with the numerical model of the experimental system. Next, we compared the results to the damage behavior of the experimentally determined laminated composite femoral component to assess which parameter set most accurately predicted the actual damage development behavior. We then applied the best-fitting parameter set to analyze simulated in situ composite femoral components. Results showed that this methodology efficiently and accurately predicted damage initiation and propagation. This research demonstrates how analytical and numerical models may be used before conducting extensive experimental tests as initial tools to evaluate components for the design of composite hip implants that possess a high level of damage resistance and damage tolerance.

Equipment Failure Analysis↗