We describe a new computational method, FRODA (framework rigidity optimized dynamic algorithm), for exploring the internal mobility of proteins. The rigid regions in the protein are first determined, and then replaced by ghost templates which are used to guide the movements of the atoms in the protein. Using random moves, the available conformational phase space of a 100 residue protein can be well explored in approximately 10-100 min of computer time using a single processor. All of the covalent, hydrophobic and hydrogen bond constraints are maintained, and van der Waals overlaps are avoided, throughout the simulation. We illustrate the results of a FRODA simulation on barnase, and show that good agreement is obtained with nuclear magnetic resonance experiments. We additionally show how FRODA can be used to find a pathway from one conformation to another. This directed dynamics is illustrated with the protein dihydrofolate reductase. M This article features online multimedia enhancements
Although biofilm-based fungal infections are an important cause of morbidity and mortality in patients, there is no standardized method for the in vitro evaluation of the drug susceptibility of biofilms. We investigated a high-throughput method for determining the susceptibility of Candida albicans biofilms that uses the oxidation reduction indicator Alamar blue (AB). Biofilms from the tested Candida albicans strains were markedly resistant to amphotericin B (AMB), nystatin (NYT), fluconazole (FLC) and 5-fluorouracil (5FC), but susceptible to Conflikt disinfectant. The latter was used in comparative studies of AB reduction with two other methods for assessing in vitro drug susceptibility i.e., 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction and enumeration of viable colony counts (CFU/ml). AB results correlated well with XTT (r=0.88-0.93) and CFU/ml (r=0.93-0.99) for all four C. albicans test strains. This simple, reproducible method for determining in vitro drug susceptibility should facilitate discovery of antifungals active against Candida biofilms.
No abstract
Observations, experiments and simulations often generate large numbers of snapshots of configurations of complex many-body systems. It is important to find methods of extracting useful information from these ensembles of snapshots in order to document the motion as the system evolves in time. Some of the most interesting information is contained in the relative motion of individual constituents, rather than their absolute motion. We present a novel statistical method for identifying hierarchies of plastically connected objects in a system from a series of two or more snapshot configurations. These plastic clusters are distinctive in that although their members tend to remain loosely connected, the clusters may be deformed plastically. This method is demonstrated for a number of systems, including an exactly soluble freely jointed polymer chain model, a two-dimensional simulation of two species of interacting bodies and a protein. These concepts are implemented as TIMME, the Tool for Identifying Mobility in Macromolecular Ensembles.
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