Protein Structure Prediction: The Next Generation

Over the last 10-15 years a general understanding of the chemical reaction of protein folding has emerged from statistical mechanics. The lessons learned from protein folding kinetics based on energy landscape ideas have benefited protein structure prediction, in particular the development of coarse grained models. We survey results from blind structure prediction. We explore how second generation prediction energy functions can be developed by introducing information from an ensemble of previously simulated structures. This procedure relies on the assumption of a funnelled energy landscape keeping with the principle of minimal frustration. First generation simulated structures provide an improved input for associative memory energy functions in comparison to the experimental protein structures chosen on the basis of sequence alignment

Protein Structure Prediction Using Basin-Hopping

Associative memory Hamiltonian structure prediction potentials are not overly rugged, thereby suggesting their landscapes are like those of actual proteins. In the present contribution we show how basin-hopping global optimization can identify low-lying minima for the corresponding mildly frustrated energy landscapes. For small systems the basin-hopping algorithm succeeds in locating both lower minima and conformations closer to the experimental structure than does molecular dynamics with simulated annealing. For large systems the efficiency of basin-hopping decreases for our initial implementation, where the steps consist of random perturbations to the Cartesian coordinates. We implemented umbrella sampling using basin-hopping to further confirm when the global minima are reached. We have also improved the energy surface by employing bioinformatic techniques for reducing the roughness or variance of the energy surface. Finally, the basin-hopping calculations have guided improvements in the excluded volume of the Hamiltonian, producing better structures. These results suggest a novel and transferable optimization scheme for future energy function development

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Nanostructures, Technology, Research, and Applications

Contains reports on twenty research projects and a list of publications.Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant ECS-94-07078Semiconductor Research CorporationU.S. Army Research Office Grant DAAH04-95-1-0564Defense Advanced Research Projects Agency/Naval Air Systems Command Contract N00019-95-K-0131National Aeronautics and Space Administration Contract NAS8-38249National Aeronautics and Space Administration Grant NAGW-2003IBM Corporation Contract 1622National Science Foundation Graduate FellowshipU.S. Navy - Office of Naval Research Grant N00014-95-1-1297U.S. Army Research Office Contract DAAH04-94-G-0377U.S. Air Force - Office of Scientific Research Grant F49620-92-J-0064U.S. Air Force - Office of Scientific Research Grant F49620-95-1-0311National Science Foundation Contract DMR 94-0034U.S. Air Force - Office of Scientific Research Contract F49620-96-0126Harvard-Smithsonian Astrophysical Observatory Contract SV630304National Aeronautics and Space Administration Grant NAG5-5105Los Alamos National Laboratory Contract E57800017-9

Nanostructures Technology, Research, and Applications

Contains reports on twenty-four research projects and a list of publications.Joint Services Electronics Program Grant DAAHO4-95-1-0038Defense Advanced Research Projects Agency/Semiconductor Research Corporation SA1645-25508PGU.S. Army Research Office Grant DAAHO4-95-1-0564Defense Advanced Research Projects Agency/U.S. Navy - Naval Air Systems Command Contract N00019-95-K-0131Suss Advanced Lithography P. O. 51668National Aeronautics and Space Administration Contract NAS8-38249National Aeronautics and Space Administration Grant NAGW-2003Defense Advanced Research Projects Agency/U.S. Army Research Office Grant DAAHO4-951-05643M CorporationDefense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Contract N66001-97-1-8909National Science Foundation Graduate FellowshipU.S. Army Research Office Contract DAAHO4-94-G-0377National Science Foundation Contract DMR-940034National Science Foundation Grant DMR 94-00334Defense Advanced Research Projects Agency/U.S. Air Force - Office of Scientific Research Contract F49620-96-1-0126Harvard-Smithsonian Astrophysical Observatory Contract SV630304National Aeronautics and Space Administration Grant NAG5-5105Los Alamos National Laboratory Contract E57800017-9GSouthwest Research Institute Contract 83832MIT Lincoln Laboratory Advanced Concepts ProgramMIT Lincoln Laboratory Contract BX-655

Impact of an antimicrobial stewardship intervention in India: Evaluation of post-prescription review and feedback as a method of promoting optimal antimicrobial use in the intensive care units of a tertiary-care hospital

OBJECTIVE: Antimicrobial stewardship programs (ASPs) are effective in developed countries. In this study, we assessed the effectiveness of an infectious disease (ID) physician-driven post-prescription review and feedback as an ASP strategy in India, a low middle-income country (LMIC). DESIGN AND SETTING: This prospective cohort study was carried out for 18 months in 2 intensive care units of a tertiary-care hospital, consisting of 3 phases: baseline, intervention, and follow up. Each phase spanned 6 months. PARTICIPANTS: Patients aged ≥15 years receiving 48 hours of study antibiotics were recruited for the study. METHODS: During the intervention phase, an ID physician reviewed the included cases and gave alternate recommendations if the antibiotic use was inappropriate. Acceptance of the recommendations was measured after 48 hours. The primary outcome of the study was days of therapy (DOT) per 1,000 study patient days (PD). RESULTS: Overall, 401 patients were recruited in the baseline phase, 381 patients were recruited in the intervention phase, and 379 patients were recruited in the follow-up phase. Antimicrobial use decreased from 831.5 during the baseline phase to 717 DOT per 1,000 PD in the intervention phase (P \u3c .0001). The effect was sustained in the follow-up phase (713.6 DOT per 1,000 PD). De-escalation according to culture susceptibility improved significantly in the intervention phase versus the baseline phase (42.7% vs 23.6%; P \u3c .0001). Overall, 73.3% of antibiotic prescriptions were inappropriate. Recommendations by the ID team were accepted in 60.7% of the cases. CONCLUSION: The ID physician-driven implementation of an ASP was successful in reducing antibiotic utilization in an acute-care setting in India