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This thesis describes studies performed to measure the deformation of the human acetabulum during weight bearing. This work is then extended to measure the effect of three surface coatings on the relative motion between the pelvis and cementless acetabular cups. The soft-tissue and bony anatomy of the hip joint is described with particular attention to the muscles controlling joint motion. An additional chapter is devoted to the biomechanics of gait and electromyographic measurement of muscular activity during normal walking. This is followed by a review of the biomechanics of the hip joint and the contribution of studies performed using instrumented hip prostheses. The author then presents a new approach to the prediction of muscle forces during walking. A conventional engineering analysis is presented relating the intersegmental components of force and moment acting across the hip joint to forces developed by individual muscles during the early stance phase of the gait cycle. Various strategies are employed to solve this indeterminate mechanical problem using data derived from quantitative electromyography, the kinematics and biomechanics of gait and intravital recordings of hip joint forces. Through use of mathematical optimization, a solution is found that is consistent with both the engineering analysis and quantitative electromyographic data. Experiments are reported utilizing four cadaveric specimens in which the position and loading of the hip joint were recreated using instrumented cables and loading fixtures. Measurements of acetabular deformation are reported at 11 sites on each specimen. These data are recorded on a computer disk which accompanies this thesis. The overall pattern of deformation is found to be consistent with biaxial bending of the pelvis over a fulcrum formed by the femoral head. The second part of the thesis describes an experiment performed to determine whether external coatings influence the stability of cementless acetabular cups implanted in the acetabulum. A standard design of an acetabular cup is developed on the basis of anatomic studies of cadaveric pelves. Experiments are described using cups with three external coatings: spherical Co-Cr beads, plasma-sprayed titanium and 1 hydroxyapatite. These components were implanted into the acetabuli of five fresh cadaveric pelves and loaded in three-point bending. Interface motion was measured at the dome, the acetabular floor and the cotyloid notch of each specimen during loading to 2000 N. The results of this study are recorded on a computer disk (see Appendix). These data showed that the surface coating dramatically influences the interface motion of acetabular cups. Implant motion was found to be site-specific and appeared to be determined, primarily, by the interaction of elastic deformation of the pelvis and frictional conditions at the shell/bone interface.

A high number of revision hip replacement operations are currently performed due to loosening of the primary implant. The loading imposed on the prosthetic joint and its fixation mechanisms may be one of the many factors contributing to the loosening process. Previous work to determine hip joint loading has concentrated on gait, stair negotiation and rising from a chair. However, since patients often comment on the difficulty of getting into and out of a car and bath, these activities are also included in the current project. The 3 orthogonal components of hip joint force have been calculated for 16 postoperative hip replacement patients between one and two years after surgery and also for 10 age-matched normals. A biomechanical model of the lower limb was developed including 37 muscle elements. Algorithms were incorporated to correct for curved muscle paths, providing realistic muscle moment arms with changing joint angle configuration. An optimization routine which minimizes the o verall maximum muscle stress was incorporated to determine muscle forces which were then used in the calculation of joint force. The model utilizes anatomical muscle and bone data, kinematics measured using a 6 camera Vicon motion analysis system and ground reaction forces measured using force platforms. In validity tests, the predicted muscle activity patterns for normal subjects were found to be consistent with published EMG data for most muscles. The mean peak resultant hip joint force of 3.8 times body weight calculated for the patients during gait at 1.01 m/s was consistent with the results published for patients with instrumented hip prostheses at a measurement time of more than 12 months after surgery. The maximum mean peak resultant hip joint force determined for patients was 5 times body weight, calculated at the left hip when getting out of the passenger side of a right hand drive car. A simple calculation of torsional moment about the stem of the femoral component during this and other activities showed it to be close to or to exceed the experimentally determined limits of torsional strength of implant fixations, reported in the literature. The maximum mean peak resultant hip joint force calculated for normals was 6.3 times body weight, determined at the left hip on getting into the passenger side of a right hand drive car. It is suggested that car entry and exit and other activities should be performed in safer styles rid that the results of this thesis should be incorporated into the design and testing of hip prostheses.

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<p>Biological macromolecules can rearrange interdomain orientations when binding to various partners. Interdomain dynamics serve as a molecular mechanism to guide the transitions between orientations. However, our understanding of interdomain dynamics is limited because a useful description of interdomain motions requires an estimate of the probabilities of interdomain conformations, increasing complexity of the problem.</p><p>Staphylococcal protein A (SpA) has five tandem protein-binding domains and four interdomain linkers. The domains enable Staphylococcus aureus to evade the host immune system by binding to multiple host proteins including antibodies. Here, I present a study of the interdomain motions of two adjacent domains in SpA. NMR spin relaxation experiments identified a 6-residue flexible interdomain linker and interdomain motions. To quantify the anisotropy of the distribution of interdomain orientations, we measured residual dipolar couplings (RDCs) from the two domains with multiple alignments. The N-terminal domain was directly aligned by a lanthanide ion and not influenced by interdomain motions, so it acted as a reference frame to achieve motional decoupling. We also applied {\it de novo} methods to extract spatial dynamic information from RDCs and represent interdomain motions as a continuous distribution on the 3D rotational space. Significant anisotropy was observed in the distribution, indicating the motion populates some interdomain orientations more than others. Statistical thermodynamic analysis of the observed orientational distribution suggests that it is among the energetically most favorable orientational distributions for binding to antibodies. Thus, the affinity is enhanced by a pre-posed distribution of interdomain orientations while maintaining the flexibility required for function.</p><p>The protocol described above can be applied to other biological systems in general. Protein molecule calmodulin and RNA molecule trans-activation response element (TAR) also have intensive interdomain motions with relative small intradomain dynamics. Their interdomain motions were studied using our method based on published RDC data. Our results were consistent with literature results in general. The differences could be due to previous studies' use of physical models, which contain assumptions about potential energy and thus introduced non-experimental information into the interpretations.</p> / Dissertation

<p>Electrostatic interactions are of fundamental importance in determining the structure and stability of macromolecules. For example, charge-charge interactions modulate the folding and binding of proteins and influence protein solubility. Electrostatic interactions are highly variable and can be both favorable and unfavorable. The ability to quantify these interactions is challenging but vital to understanding the detailed balance and major roles that they have in different proteins and biological processes. Measuring pKa values of ionizable groups provides a sensitive method for experimentally probing the electrostatic properties of a protein. </p><p>pKa values report the free energy of site-specific proton binding and provide a direct means of studying protein folding and pH-dependent stability. Using a combination of NMR, circular dichroism, and fluorescence spectroscopy along with singular value decomposition, we investigated the contributions of electrostatic interactions to the thermodynamic stability and folding of the protein subunit of Bacillus subtilis ribonuclease P, P protein. Taken together, the results suggest that unfavorable electrostatics alone do not account for the fact that P protein is intrinsically unfolded in the absence of ligand because the pKa differences observed between the folded and unfolded state are small. Presumably, multiple factors encoded in the P protein sequence account for its IUP property, which may play an important role in its function.</p> / Dissertation

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