Enumeration of cubic lattice walks by contact class

Self-avoiding walks on a three-dimensional (3D) simple cubic lattice are often used to model polymers, especially proteins. The Hamiltonian is generally taken to be a function of contacts between sequentially nonadjacent residues. The set of all conformations having a particular set of contacts occupies the same energy level, and one would like to estimate the degeneracy or chain entropy of the level. Degeneracies observed in an exhaustive enumeration of short chain configurations are fitted to simple empirical formulas depending on the length of the chain, the number of contacts, and statistics related to the particular set of contacts. © 2000 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69928/2/JCPSA6-112-24-11065-1.pd

Lattice models of protein folding permitting disordered native states

Self-avoiding lattice walks are often used as minimalist models of proteins. Typically, the polypeptide chain is represented as a lattice walk with each amino acid residue lying on a lattice point, and the Hamiltonian being a sum of interactions between pairs of sequentially nonadjacent residues on adjacent points. Interactions depend on the types of the two residues, and there are usually two or more types. A sequence is said to fold to a particular “native” conformation if the ground state is nondegenerate, i.e., that native conformation is the unique global energy minimum conformation. However, real proteins have some flexibility in the folded state. If this is permitted in a lattice model, the most stably and cooperatively folding sequences have very disordered native states unless the Hamiltonian either favors only a few specific interactions or includes a solvation term. The result points the way toward qualitatively more realistic lattice models for protein folding. © 2002 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70382/2/JCPSA6-116-5-2261-1.pd

A protein folding potential that places the native states of a large number of proteins near a local minimum

BACKGROUND: We present a simple method to train a potential function for the protein folding problem which, even though trained using a small number of proteins, is able to place a significantly large number of native conformations near a local minimum. The training relies on generating decoys by energy minimization of the native conformations using the current potential and using a physically meaningful objective function (derivative of energy with respect to torsion angles at the native conformation) during the quadratic programming to place the native conformation near a local minimum. RESULTS: We also compare the performance of three different types of energy functions and find that while the pairwise energy function is trainable, a solvation energy function by itself is untrainable if decoys are generated by minimizing the current potential starting at the native conformation. The best results are obtained when a pairwise interaction energy function is used with solvation energy function. CONCLUSIONS: We are able to train a potential function using six proteins which places a total of 42 native conformations within ~4 Å rmsd and 71 native conformations within ~6 Å rmsd of a local minimum out of a total of 91 proteins. Furthermore, the threading test using the same 91 proteins ranks 89 native conformations to be first and the other two as second

Fold Recognition via a Tree

Recently, we developed a pairwise structural alignment algorithm using realistic structural and environmental information (SAUCE). In this paper, we at first present an automatic fold hierarchical classification based on SAUCE alignments. This classification enables us to build a fold tree containing different levels of multiple structural profiles. Then a tree-based fold search algorithm is described. We applied this method to a group of structures with sequence identity less than 35% and did a series of leave one out tests. These tests are approximately comparable to fold recognition tests on superfamily level. Results show that fold recognition via a fold tree can be faster and better at detecting distant homologues than classic fold recognition methods.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63155/1/cmb.2006.13.1565.pd

Potential Energy Function for Continuous State Models of Globular Proteins

One of the approaches to protein structure prediction is to obtain energy functions which can recognize the native conformation of a given sequence among a zoo of conformations. The discriminations can be done by assigning the lowest energy to the native conformation, with the guarantee that the native is in the zoo. Well-adjusted functions, then, can be used in the search for other (near-) natives. Here the aim is the discrimination at relatively high resolution (RMSD difference between the native and the closest nonnative is around 1 Å) by pairwise energy potentials. The potential is trained using the experimentally determined native conformation of only one protein, instead of the usual large survey over many proteins. The novel feature is that the native structure is compared to a vastly wider and more challenging array of nonnative structures found not only by the usual threading procedure, but by wide-ranging local minimization of the potential. Because of this extremely demanding search, the native is very close to the apparent global minimum of the potential function. The global minimum property holds up for one other protein having 60% sequence identity, but its performance on completely dissimilar proteins is of course much weaker.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63101/1/106652700750050835.pd

Ethics review: Dark angels – the problem of death in intensive care

Critical care medicine has expanded the envelope of debilitating disease through the application of an aggressive and invasive care plan, part of which is designed to identify and reverse organ dysfunction before it proceeds to organ failure. For a select patient population, this care plan has been remarkably successful. But because patient selection is very broad, critical care sometimes yields amalgams of life in death: the state of being unable to participate in human life, unable to die, at least in the traditional sense. This work examines the emerging paradox of somatic versus brain death and why it matters to medical science

Selection of process parameters for sodium removal via the water vapor nitrogen process

For the vapor phase of the WVN process the 160 to 190{sup 0}F temperature limit is shown to be well within the 145 to 208{sup 0}F minimum/maximum range. Decreasing process time by expansion of the temperature range is not expected to aid processing. The most productive area for improvement would be an increase in the water vapor concentration above the present 5% level. However, this would require confirmatory testing before approved use. The rinsing process was shown to be mainly controlled by component crevice geometry. Improvements in rinse time may be made by increasing the water temperature, but the concern over the caustic stress corrosion cracking will tend to limit the available increase. Although directed jets or sprays of rinse flows was not recommended, methods were suggested for conserving rinse water. Drying (as well as heating and cooling) of components was again shown to be constrained mostly by individual geometry and not processing parameters. A gas only, vacuum only, or a combination of the two modes were shown to be generally accepted methods. The hot gas only mode was recommended for its simplicity

Recognizing protein folds by cluster distance geometry

Cluster distance geometry is a recent generalization of distance geometry whereby protein structures can be described at even lower levels of detail than one point per residue. With improvements in the clustering technique, protein conformations can be summarized in terms of alternative contact patterns between clusters, where each cluster contains four sequentially adjacent amino acid residues. A very simple potential function involving 210 adjustable parameters can be determined that favors the native contacts of 31 small, monomeric proteins over their respective sets of nonnative contacts. This potential then favors the native contacts for 174 small, monomeric proteins that have low sequence identity with any of the training set. A broader search finds 698 small protein chains from the Protein Data Bank where the native contacts are preferred over all alternatives, even though they have low sequence identity with the training set. This amounts to a highly predictive method for ab initio protein folding at low spatial resolution. Proteins 2005;. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48690/1/20488_ftp.pd

Failures of inverse folding and threading with gapped alignment

To calculate the tertiary structure of a protein from its amino acid sequence, the thermodynamic approach requires a potential function of sequence and conformation that has its global minimum at the native conformation for many different proteins. Here we study the behavior of such functions for the simplest model system that still has some of the features of the protein folding problem, namely two-dimensional square lattice chain configurations involving two residue types. First we show that even the given contact potential, which by definition is used to identify the folding sequences and their unique native conformations, cannot always correctly select which sequences will fold to a given structure. Second, we demonstrate that the given contact potential is not always able to favor the native alignment of a native sequence on its own native conformation over other gapped alignments of different folding sequences onto that same conformation. Because of these shortcomings, even in this simple model system in which all conformations and all native sequences are known and determined directly by the given potential, we must reexamine our expectations for empirical potentials used for inverse folding and gapped alignment on more realistic representations of proteins. © 1996 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38525/1/6_ftp.pd