High Performance Computing Systems and Applications, 1998
Molecular docking has become a fundamental tool in both the process of drug discovery and the und... more Molecular docking has become a fundamental tool in both the process of drug discovery and the understanding of protein structure and function. While much effort has gone into faster and more effective automated docking algorithms, the visualization of molecular structures remains an important tool for the correct interpretation of structural predictions. The integration of the Research docking algorithm into the Virtual Reality facility at the Cornell Theory Center offers a unique tool for understanding of protein-ligand interactions. The docking program Research is a fast Monte Carlo docking method employing a full force-field interaction model to represent molecular interactions. The program is integrated as a function call within the VR/3D workspace environment and connected with a sophisticated molecular viewer that displays docking results in real time. The workspace viewer allows the user to change perspective, style of molecular display, and parameters of the Research algorithm during the docking procedure. Multiple docking processes can be run simultaneously and interactively attached or detached from the viewing workspace. The integrated docking/viewing environment is not only a practical tool for drug discovery and design, but also offers an inside look at the molecular docking process.
A physical map of a genome is an essential guide for navigation, allowing the location of any gen... more A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.
Transition state analogue boronic acid inhibitors mimicking the structures and interactions of go... more Transition state analogue boronic acid inhibitors mimicking the structures and interactions of good penicillin substrates for the TEM-1 beta-lactamase of Escherchia coli were designed using graphic analyses based on the enzyme's 1.7 A crystallographic structure. The synthesis of two of these transition state analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, as designed, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1 beta-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them as among the most potent competitive inhibitors yet reported for a beta-lactamase. The best inhibitor of the current series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, K(I) = 5.9 nM), which resembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described. In addition to verifying the design features, these two structures show interesting and unanticipated changes in the active site area, including strong hydrogen bond formation, water displacement, and rearrangement of side chains. The structures provide new insights into the further design of this potent class of beta-lactamase inhibitors.
In this paper, we propose an efficient method for long-term monitoring of a wide variety of marin... more In this paper, we propose an efficient method for long-term monitoring of a wide variety of marine mammals and human related activities using hydrophone data. The proposed method uses a combination of a two-stage denoising process followed by a new event detection function that estimates temporal predictability. The detection function utilizes long-term and short-term predictions in order to detect various acoustic events from the background noise. The first stage of the denoising process uses temporal decomposition ...
CRANK is a novel suite for automated macromolecular structure solution and uses recently develope... more CRANK is a novel suite for automated macromolecular structure solution and uses recently developed programs for substructure detection, refinement, and phasing. CRANK utilizes methods for substructure detection and phasing and combines them with existing crystallographic programs for density modification and automated model building in a convenient and easy-to-use CCP4i graphical interface. The data model used conforms to the XML eXtensible Markup Language specification and works as a common language to communicate data between many different applications inside and outside of the suite. The application of CRANK on various test cases has yielded promising results: with minimal user input, CRANK can produce better quality solutions over currently available programs.
CRANK is a novel suite for automated macromolecular structure solution and uses recently develope... more CRANK is a novel suite for automated macromolecular structure solution and uses recently developed programs for substructure detection, refinement, and phasing. CRANK utilizes methods for substructure detection and phasing and combines them with existing crystallographic programs for density modification and automated model building in a convenient and easy-to-use CCP4i graphical interface. The data model used conforms to the XML eXtensible Markup Language specification and works as a common language to communicate data between many different applications inside and outside of the suite. The application of CRANK on various test cases has yielded promising results: with minimal user input, CRANK can produce better quality solutions over currently available programs.
To describe a case of successful treatment of acute retinal necrosis with a combination of antivi... more To describe a case of successful treatment of acute retinal necrosis with a combination of antivirals and intravenous immunoglobulin. This is a case report of a 77-year-old white man diagnosed with unilateral acute retinal necrosis. Combination therapy with systemic antivirals, prophylactic laser retinopexy, and intravenous immunoglobulin halted progression of retinitis and preserved visual acuity. Acute retinal necrosis is an aggressive disease with significant risk of vision loss even when treated with appropriate therapy. In this report, the authors describe a case of successful treatment with a combination of systemic antivirals and intravenous immunoglobulin. Intraocular antiviral injection plus systemic treatment remain to be a more cost-effective option.
The goal of docking is to predict binding interactions between molecules. We are primarily intere... more The goal of docking is to predict binding interactions between molecules. We are primarily interested in docking as a tool for the structure-based design of new ligands that could serve as lead compounds for drug development. The program BOXSEARCH uses a Monte Carlo algorithm to explore the relative orientation and position of two molecules. Multiple runs are carried out from
The binding positions of six small-molecule ligands in their complexes with target proteins were ... more The binding positions of six small-molecule ligands in their complexes with target proteins were predicted using our Research docking program for the CASP2 challenge. Research uses a Monte Carlo procedure with pairwise energies and allows for the conformational searching of ligand torsional space. We were able to predict 2 of the 5 noncovalent complexes within 2 A root-mean-square (RMS) of the experimental structures as ranked by interaction energy or by a score calculated using our interaction evaluation program, Out-rank. In addition, for 4 of the 5 noncovalent structures we found a docking within 2 A RMS of the experimental structure within the top 20 dockings as ranked by energy. The main limitation in our approach is in the ability of the energy function and Outrank to discriminate among the lowest energy dockings. On the other hand, our success in exploring the multi-dimensional docking space of position, orientation and conformation is encouraging.
ABSTRACT Structural models for three alkaline conformers of yeast iso-1-ferricytochrome c have be... more ABSTRACT Structural models for three alkaline conformers of yeast iso-1-ferricytochrome c have been calculated from the atomic coordinates of the native protein through the use of molecular dynamics simulation. In the three models produced by this work, the Met80 axial ligand to the heme iron has been replaced by either Lys72, Lys73, or Lys79, and the related changes in structure of the cyto-chrome are described. The principal changes in cytochrome structure predicted to result from this pH-linked change in axial ligation involve location of residues 70–80, a region of the protein sequence that is phylogenetically conserved. The remainder of the protein fold in each model is essentially unchanged from the structure of the native protein, which is consistent with available spectroscopic information. The observation that this highly conserved region is apparently integrally involved in this conformational change may be interpreted as indicating a possible physiological role for the pH-linkage of ferricytochrome c structure.
High Performance Computing Systems and Applications, 1998
Molecular docking has become a fundamental tool in both the process of drug discovery and the und... more Molecular docking has become a fundamental tool in both the process of drug discovery and the understanding of protein structure and function. While much effort has gone into faster and more effective automated docking algorithms, the visualization of molecular structures remains an important tool for the correct interpretation of structural predictions. The integration of the Research docking algorithm into the Virtual Reality facility at the Cornell Theory Center offers a unique tool for understanding of protein-ligand interactions. The docking program Research is a fast Monte Carlo docking method employing a full force-field interaction model to represent molecular interactions. The program is integrated as a function call within the VR/3D workspace environment and connected with a sophisticated molecular viewer that displays docking results in real time. The workspace viewer allows the user to change perspective, style of molecular display, and parameters of the Research algorithm during the docking procedure. Multiple docking processes can be run simultaneously and interactively attached or detached from the viewing workspace. The integrated docking/viewing environment is not only a practical tool for drug discovery and design, but also offers an inside look at the molecular docking process.
A physical map of a genome is an essential guide for navigation, allowing the location of any gen... more A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.
Transition state analogue boronic acid inhibitors mimicking the structures and interactions of go... more Transition state analogue boronic acid inhibitors mimicking the structures and interactions of good penicillin substrates for the TEM-1 beta-lactamase of Escherchia coli were designed using graphic analyses based on the enzyme's 1.7 A crystallographic structure. The synthesis of two of these transition state analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, as designed, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1 beta-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them as among the most potent competitive inhibitors yet reported for a beta-lactamase. The best inhibitor of the current series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, K(I) = 5.9 nM), which resembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described. In addition to verifying the design features, these two structures show interesting and unanticipated changes in the active site area, including strong hydrogen bond formation, water displacement, and rearrangement of side chains. The structures provide new insights into the further design of this potent class of beta-lactamase inhibitors.
In this paper, we propose an efficient method for long-term monitoring of a wide variety of marin... more In this paper, we propose an efficient method for long-term monitoring of a wide variety of marine mammals and human related activities using hydrophone data. The proposed method uses a combination of a two-stage denoising process followed by a new event detection function that estimates temporal predictability. The detection function utilizes long-term and short-term predictions in order to detect various acoustic events from the background noise. The first stage of the denoising process uses temporal decomposition ...
CRANK is a novel suite for automated macromolecular structure solution and uses recently develope... more CRANK is a novel suite for automated macromolecular structure solution and uses recently developed programs for substructure detection, refinement, and phasing. CRANK utilizes methods for substructure detection and phasing and combines them with existing crystallographic programs for density modification and automated model building in a convenient and easy-to-use CCP4i graphical interface. The data model used conforms to the XML eXtensible Markup Language specification and works as a common language to communicate data between many different applications inside and outside of the suite. The application of CRANK on various test cases has yielded promising results: with minimal user input, CRANK can produce better quality solutions over currently available programs.
CRANK is a novel suite for automated macromolecular structure solution and uses recently develope... more CRANK is a novel suite for automated macromolecular structure solution and uses recently developed programs for substructure detection, refinement, and phasing. CRANK utilizes methods for substructure detection and phasing and combines them with existing crystallographic programs for density modification and automated model building in a convenient and easy-to-use CCP4i graphical interface. The data model used conforms to the XML eXtensible Markup Language specification and works as a common language to communicate data between many different applications inside and outside of the suite. The application of CRANK on various test cases has yielded promising results: with minimal user input, CRANK can produce better quality solutions over currently available programs.
To describe a case of successful treatment of acute retinal necrosis with a combination of antivi... more To describe a case of successful treatment of acute retinal necrosis with a combination of antivirals and intravenous immunoglobulin. This is a case report of a 77-year-old white man diagnosed with unilateral acute retinal necrosis. Combination therapy with systemic antivirals, prophylactic laser retinopexy, and intravenous immunoglobulin halted progression of retinitis and preserved visual acuity. Acute retinal necrosis is an aggressive disease with significant risk of vision loss even when treated with appropriate therapy. In this report, the authors describe a case of successful treatment with a combination of systemic antivirals and intravenous immunoglobulin. Intraocular antiviral injection plus systemic treatment remain to be a more cost-effective option.
The goal of docking is to predict binding interactions between molecules. We are primarily intere... more The goal of docking is to predict binding interactions between molecules. We are primarily interested in docking as a tool for the structure-based design of new ligands that could serve as lead compounds for drug development. The program BOXSEARCH uses a Monte Carlo algorithm to explore the relative orientation and position of two molecules. Multiple runs are carried out from
The binding positions of six small-molecule ligands in their complexes with target proteins were ... more The binding positions of six small-molecule ligands in their complexes with target proteins were predicted using our Research docking program for the CASP2 challenge. Research uses a Monte Carlo procedure with pairwise energies and allows for the conformational searching of ligand torsional space. We were able to predict 2 of the 5 noncovalent complexes within 2 A root-mean-square (RMS) of the experimental structures as ranked by interaction energy or by a score calculated using our interaction evaluation program, Out-rank. In addition, for 4 of the 5 noncovalent structures we found a docking within 2 A RMS of the experimental structure within the top 20 dockings as ranked by energy. The main limitation in our approach is in the ability of the energy function and Outrank to discriminate among the lowest energy dockings. On the other hand, our success in exploring the multi-dimensional docking space of position, orientation and conformation is encouraging.
ABSTRACT Structural models for three alkaline conformers of yeast iso-1-ferricytochrome c have be... more ABSTRACT Structural models for three alkaline conformers of yeast iso-1-ferricytochrome c have been calculated from the atomic coordinates of the native protein through the use of molecular dynamics simulation. In the three models produced by this work, the Met80 axial ligand to the heme iron has been replaced by either Lys72, Lys73, or Lys79, and the related changes in structure of the cyto-chrome are described. The principal changes in cytochrome structure predicted to result from this pH-linked change in axial ligation involve location of residues 70–80, a region of the protein sequence that is phylogenetically conserved. The remainder of the protein fold in each model is essentially unchanged from the structure of the native protein, which is consistent with available spectroscopic information. The observation that this highly conserved region is apparently integrally involved in this conformational change may be interpreted as indicating a possible physiological role for the pH-linkage of ferricytochrome c structure.
Uploads