Biomedical subjects

Moon K Kim

Publications and source records attributed to Moon K Kim.

10 recordsLinked to original sources

PubMed2007

Steiner minimal trees, twist angles, and the protein folding problem.

The Steiner Minimal Tree (SMT) problem determines the minimal length network for connecting a given set of vertices in three-dimensional space. SMTs have been shown to be useful in the geometric modeling and characterization of proteins. Even though the SMT problem is an NP-Hard Optimization problem, one can define planes within the amino acids that have a surprising regularity property for the twist angles of the planes. This angular property is quantified for all amino acids through the Steiner tree topology structure. The twist angle properties and other associated geometric properties unique for the remaining amino acids are documented in this paper. We also examine the relationship between the Steiner ratio rho and the torsion energy in amino acids with respect to the side chain torsion angle chi(1). The rho value is shown to be inversely proportional to the torsion energy. Hence, it should be a useful approximation to the potential energy function. Finally, the Steiner ratio is used to evaluate folded and misfolded protein structures. We examine all the native proteins and their decoys at http://dd.stanford.edu. and compare their Steiner ratio values. Because these decoy structures have been delicately misfolded, they look even more favorable than the native proteins from the potential energy viewpoint. However, the rho value of a decoy folded protein is shown to be much closer to the average value of an empirical Steiner ratio for each residue involved than that of the corresponding native one, so that we recognize the native folded structure more easily. The inverse relationship between the Steiner ratio and the energy level in the protein is shown to be a significant measure to distinguish native and decoy structures. These properties should be ultimately useful in the ab initio protein folding prediction.

Amino Acids↗

PubMed2006

Head-mounted goggles for murine form deprivation myopia.

Recently a murine model has been developed for use in form deprivation myopia experiments. Due to the small size of the head and eye, methods to blur visual input to the mouse eye are challenging. Previous methods to induce form deprivation include lid suture and gluing diffuser goggles directly to the fur around the eye. In this paper we describe a new method of goggling using a head pedestal and goggle, which improves compliance and allows for better ocular health. Nob mice, previously shown to be highly susceptible to form deprivation myopia, were used for these experiments. Immediately following baseline refraction using an infrared automated photorefractor, mice were either goggled with a diffuser attached directly to the fur or with a head-mounted goggling apparatus. The goggle apparatus consists of five main components: goggle and frame, head pedestal, acrylic cube for stabilization, and balancing bar. Mice were goggled for 2 weeks in which ocular health and goggle position was monitored and then had a final refraction. The use of head-mounted goggles resulted in 75% fewer instances of goggle loss and 55% fewer ocular complications compared to goggles glued to the fur. Both goggling methods induced a myopic shift of approximately 5 diopters. The head-mounted goggle apparatus provides an improved method for inducing form deprivation in mice and offers the ability to easily take repeated refractive measurements as well as allowing for the use of defocusing lenses.

Animals↗

PubMed2006

Structural and functional MRI reveals multiple retinal layers.

MRI is a noninvasive diagnostic modality that reveals anatomy, physiology, and function in vivo without depth limitation or optical interference. MRI application to the retina, however, remains challenging. We improved spatial resolution to resolve layer-specific structure and functional responses in the retina and confirmed the laminar resolution in an established animal model of retinal degeneration. Structural MRI of normal rat retinas revealed three bands corresponding histologically to (i) the combined ganglion cell layer/inner nuclear layer plus the embedded retinal vessels, (ii) the avascular outer nuclear (photoreceptor) layer and its photoreceptor segments, and (iii) the choroidal vascular layer. Imaging with an intravascular contrast agent (gadolinium-diethylene-tri-amine-pentaacetic acid) enhanced the retinal and choroidal vascular layers bounding the retina, but not the avascular outer nuclear layer and the vitreous. Similarly, blood-oxygen-level-dependent (BOLD) functional MRI revealed layer-specific responses to hyperoxia and hypercapnia. Importantly, layer-specific BOLD responses in the two vascular layers were divergent, suggesting the two vasculatures are differentially regulated. To corroborate sensitivity and specificity, we applied layer-specific MRI to document photoreceptor degeneration in Royal College of Surgeons rats. Consistent with histology, layer-specific MRI detected degeneration of the outer nuclear layer. Surprisingly, MRI revealed increased thickness in the choroidal vascular layer and diminished BOLD responses to hyperoxia and hypercapnia in the Royal College of Surgeons rat retinas, suggesting perturbation of vascular reactivity secondary to photoreceptor loss. We conclude that MRI is a powerful investigative tool capable of resolving lamina-specific structures and functional responses in the retina as well as probing lamina-specific changes in retinal diseases.

Aging↗

PubMed2006

UMMS: constrained harmonic and anharmonic analyses of macromolecules based on elastic network models.

UMass Morph Server (UMMS) has been developed for the broad impact on the study of molecular dynamics (MD). The elastic network model (ENM) of a given macromolecule has been proven as a useful tool for analyzing thermal behaviors locally and predicting folding pathways globally. UMMS utilizes coarse-grained ENMs at various levels. These simplifications remarkably save computation time compared with all-atom MD simulations so that one can bring down massive computational problems from a supercomputer to a PC. To improve computational efficiency and physical reality of ENMs, the symmetry-constrained, rigid-cluster, hybrid and chemical-bond ENMs have been developed and implemented at UMMS. One can request both harmonic normal mode analysis of a single macromolecule and anharmonic pathway generation between two conformations of a same molecule using elastic network interpolation at http://biomechanics.ecs.umass.edu/umms.html.

Computational Biology↗

PubMed2005

A connection rule for alpha-carbon coarse-grained elastic network models using chemical bond information.

A sparser but more efficient connection rule (called a bond-cutoff method) for a simplified alpha-carbon coarse-grained elastic network model is presented. One of conventional connection rules for elastic network models is the distance-cutoff method, where virtual springs connect an alpha-carbon with all neighbor alpha-carbons within predefined distance-cutoff value. However, though the maximum interaction distance between alpha-carbons is reported as 7 angstroms, this cutoff value can make the elastic network unstable in many cases of protein structures. Thus, a larger cutoff value (>11 angstroms) is often used to establish a stable elastic network model in previous researches. To overcome this problem, a connection rule for backbone model is proposed, which satisfies the minimum condition to stabilize an elastic network. Based on the backbone connections, each type of chemical interactions is considered and added to the elastic network model: disulfide bonds, hydrogen bonds, and salt-bridges. In addition, the van der Waals forces between alpha-carbons are modeled by using the distance-cutoff method. With the proposed connection rule, one can make an elastic network model with less than 7 angstroms distance cutoff, which can reveal protein flexibility more sharply. Moreover, the normal modes from the new elastic network model can reflect conformational changes of a given protein better than ones by the distance-cutoff method. This method can save the computational cost when calculating normal modes of a given protein structure, because it can reduce the total number of connections. As a validation, six example proteins are tested. Computational times and the overlap values between the conformational change and infinitesimal motion calculated by normal mode analysis are presented. Those animations are also available at UMass Morph Server (http://biomechanics.ecs.umass.edu/umms.html).

Carbon↗

PubMed2005

Rigid-cluster models of conformational transitions in macromolecular machines and assemblies.

We present a rigid-body-based technique (called rigid-cluster elastic network interpolation) to generate feasible transition pathways between two distinct conformations of a macromolecular assembly. Many biological molecules and assemblies consist of domains which act more or less as rigid bodies during large conformational changes. These collective motions are thought to be strongly related with the functions of a system. This fact encourages us to simply model a macromolecule or assembly as a set of rigid bodies which are interconnected with distance constraints. In previous articles, we developed coarse-grained elastic network interpolation (ENI) in which, for example, only Calpha atoms are selected as representatives in each residue of a protein. We interpolate distance differences of two conformations in ENI by using a simple quadratic cost function, and the feasible conformations are generated without steric conflicts. Rigid-cluster interpolation is an extension of the ENI method with rigid-clusters replacing point masses. Now the intermediate conformations in an anharmonic pathway can be determined by the translational and rotational displacements of large clusters in such a way that distance constraints are observed. We present the derivation of the rigid-cluster model and apply it to a variety of macromolecular assemblies. Rigid-cluster ENI is then modified for a hybrid model represented by a mixture of rigid clusters and point masses. Simulation results show that both rigid-cluster and hybrid ENI methods generate sterically feasible pathways of large systems in a very short time. For example, the HK97 virus capsid is an icosahedral symmetric assembly composed of 60 identical asymmetric units. Its original Hessian matrix size for a Calpha coarse-grained model is >(300,000)(2). However, it reduces to (84)(2) when we apply the rigid-cluster model with icosahedral symmetry constraints. The computational cost of the interpolation no longer scales heavily with the size of structures; instead, it depends strongly on the minimal number of rigid clusters into which the system can be decomposed.

Algorithms↗

PubMed2003

An elastic network model of HK97 capsid maturation.

The structure of the capsid of bacteriophage HK97 has been solved at various stages of maturity by crystallography and cryo-electron microscopy, and has been reported previously in the literature. Typically the capsid assembles through polymerization and maturation processes. Maturation is composed of proteolytic cleavages to the precursor capsid (called Prohead II), expansion triggered by DNA packaging (in which the largest conformational changes of the capsid appear), and covalent cross-links of neighboring subunits to create the mature capsid called Head II. We apply a coarse-grained elastic network interpolation (ENI) to generate a feasible pathway for conformational change from Prohead II to Head II. The icosahedral symmetry of the capsid structure offers a significant computational advantage because it is not necessary to consider the whole capsid structure but only an asymmetric unit consisting of one hexamer plus an additional subunit from an adjacent pentamer. We also analyze normal modes of the capsid structure using an elastic network model which is also subject to symmetry constraints. Using our model, we can visualize the smooth evolution of capsid expansion and revisit in more detail several interesting geometric changes recognized in early experimental works such as rigid body motion of two compact domains (A and P) with two refolding extensions (N-arm and E-loop) and track the approach of the two particular residues associated with isopeptide bonds that make hexagonal cross-links in Head II. The feasibility of the predicted pathway is also supported by the results of our normal mode analysis.

Bacteriophages↗

PubMed2003

A comparison between elastic network interpolation and MD simulation of 16S ribosomal RNA.

In this paper a coarse-grained method called elastic network interpolation (ENI) is used to generate feasible transition pathways between two given conformations of the core central domain of 16S Ribosomal RNA (16S rRNA). The two given conformations are the extremes generated by a molecular dynamics (MD) simulation, which differ from each other by 10A in root-mean-square deviation (RMSD). It takes only several hours to build an ENI pathway on a 1.5GHz Pentium with 512 MB memory, while the MD takes several weeks on high-performance multi-processor servers such as the SGI ORIGIN 2000/2100. It is shown that multiple ENI pathways capture the essential anharmonic motions of millions of timesteps in a particular MD simulation. A coarse-grained normal mode analysis (NMA) is performed on each intermediate ENI conformation, and the lowest 1% of the normal modes (representing about 40 degrees of freedom (DOF)) are used to parameterize fluctuations. This combined ENI/NMA method captures all intermediate conformations in the MD run with 1.5A RMSD on average. In addition, if we restrict attention to the time interval of the MD run between the two extreme conformations, the RMSD between the closest ENI/NMA pathway and the MD results is about 1A. These results may serve as a paradigm for reduced-DOF dynamic simulations of large biological macromolecules as well as a method for the reduced-parameter interpretation of massive amounts of MD data.

Algorithms↗

PubMed2002

Efficient generation of feasible pathways for protein conformational transitions.

We develop a computationally efficient method to simulate the transition of a protein between two conformations. Our method is based on a coarse-grained elastic network model in which distances between spatially proximal amino acids are interpolated between the values specified by the two end conformations. The computational speed of this method depends strongly on the choice of cutoff distance used to define interactions as measured by the density of entries of the constant linking/contact matrix. To circumvent this problem we introduce the concept of using a cutoff based on a maximum number of nearest neighbors. This generates linking matrices that are both sparse and uniform, hence allowing for efficient computations that are independent of the arbitrariness of cutoff distance choices. Simulation results demonstrate that the method developed here reliably generates feasible intermediate conformations, because our method observes steric constraints and produces monotonic changes in virtual bond and torsion angles. Applications are readily made to large proteins, and we demonstrate our method on lactate dehydrogenase, citrate synthase, and lactoferrin. We also illustrate how this framework can be used to complement experimental techniques that partially observe protein motions.

Biophysical Phenomena↗

PubMed2002

Elastic models of conformational transitions in macromolecules.

We develop a computationally efficient and physically realistic method to simulate the transition of a macromolecule between two conformations. Our method is based on a coarse-grained elastic network model in which contact interactions between spatially proximal parts of the macromolecule are modelled with Gaussian/harmonic potentials. To delimit the interactions in such models, we introduce a cutoff to the permitted number of nearest neighbors. This generates stiffness (Hessian) matrices that are both sparse and quite uniform, hence, allowing for efficient computations. Several toy models are tested using our method to mimic simple classes of macromolecular motions such as stretching, hinge bending, shear, compression, ligand binding and nucleic acid structural transitions. Simulation results demonstrate that the method developed here reliably generates sequences of feasible intermediate conformations of macromolecules, since our method observes steric constraints and produces monotonic changes to virtual bond angles and torsion angles. A final application is made to the opening process of the protein lactoferrin.

Computer Simulation↗