Dataset Information

Monte Carlo modeling of single-molecule cytoplasmic dynein.

ABSTRACT: Molecular motors are responsible for active transport and organization in the cell, underlying an enormous number of crucial biological processes. Dynein is more complicated in its structure and function than other motors. Recent experiments have found that, unlike other motors, dynein can take different size steps along microtubules depending on load and ATP concentration. We use Monte Carlo simulations to model the molecular motor function of cytoplasmic dynein at the single-molecule level. The theory relates dynein's enzymatic properties to its mechanical force production. Our simulations reproduce the main features of recent single-molecule experiments that found a discrete distribution of dynein step sizes, depending on load and ATP concentration. The model reproduces the large steps found experimentally under high ATP and no load by assuming that the ATP binding affinities at the secondary sites decrease as the number of ATP bound to these sites increases. Additionally, to capture the essential features of the step-size distribution at very low ATP concentration and no load, the ATP hydrolysis of the primary site must be dramatically reduced when none of the secondary sites have ATP bound to them. We make testable predictions that should guide future experiments related to dynein function.

SUBMITTER: Singh MP

PROVIDER: S-EPMC1189307 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Publications

Monte Carlo modeling of single-molecule cytoplasmic dynein.

Singh Manoranjan P MP Mallik Roop R Gross Steven P SP Yu Clare C CC

Proceedings of the National Academy of Sciences of the United States of America 20050815 34

Molecular motors are responsible for active transport and organization in the cell, underlying an enormous number of crucial biological processes. Dynein is more complicated in its structure and function than other motors. Recent experiments have found that, unlike other motors, dynein can take different size steps along microtubules depending on load and ATP concentration. We use Monte Carlo simulations to model the molecular motor function of cytoplasmic dynein at the single-molecule level. Th ...[more]

PMID: 16103365

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Project description:PURPOSE:In 90 Y microsphere radioembolization (RE), accurate post-therapy imaging-based dosimetry is important for establishing absorbed dose versus outcome relationships for developing future treatment planning strategies. Additionally, accurately assessing microsphere distributions is important because of concerns for unexpected activity deposition outside the liver. Quantitative 90 Y imaging by either SPECT or PET is challenging. In 90 Y SPECT model based methods are necessary for scatter correction because energy window-based methods are not feasible with the continuous bremsstrahlung energy spectrum. The objective of this work was to implement and evaluate a scatter estimation method for accurate 90 Y bremsstrahlung SPECT/CT imaging. METHODS:Since a fully Monte Carlo (MC) approach to 90 Y SPECT reconstruction is computationally very demanding, in the present study the scatter estimate generated by a MC simulator was combined with an analytical projector in the 3D OS-EM reconstruction model. A single window (105 to 195-keV) was used for both the acquisition and the projector modeling. A liver/lung torso phantom with intrahepatic lesions and low-uptake extrahepatic objects was imaged to evaluate SPECT/CT reconstruction without and with scatter correction. Clinical application was demonstrated by applying the reconstruction approach to five patients treated with RE to determine lesion and normal liver activity concentrations using a (liver) relative calibration. RESULTS:There was convergence of the scatter estimate after just two updates, greatly reducing computational requirements. In the phantom study, compared with reconstruction without scatter correction, with MC scatter modeling there was substantial improvement in activity recovery in intrahepatic lesions (from > 55% to > 86%), normal liver (from 113% to 104%), and lungs (from 227% to 104%) with only a small degradation in noise (13% vs. 17%). Similarly, with scatter modeling contrast improved substantially both visually and in terms of a detectability index, which was especially relevant for the low uptake extrahepatic objects. The trends observed for the phantom were also seen in the patient studies where lesion activity concentrations and lesion-to-liver concentration ratios were lower for SPECT without scatter correction compared with reconstruction with just two MC scatter updates: in eleven lesions the mean uptake was 4.9 vs. 7.1 MBq/mL (P = 0.0547), the mean normal liver uptake was 1.6 vs. 1.5 MBq/mL (P = 0.056) and the mean lesion-to-liver uptake ratio was 2.7 vs. 4.3 (P = 0.0402) for reconstruction without and with scatter correction respectively. CONCLUSIONS:Quantitative accuracy of 90 Y bremsstrahlung imaging can be substantially improved with MC scatter modeling without significant degradation in image noise or intensive computational requirements.

Dataset Information

Monte Carlo modeling of single-molecule cytoplasmic dynein.

Publications

Monte Carlo modeling of single-molecule cytoplasmic dynein.

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