Dataset Information

Extending rule-based methods to model molecular geometry and 3D model resolution.

ABSTRACT: Computational modeling is an important tool for the study of complex biochemical processes associated with cell signaling networks. However, it is challenging to simulate processes that involve hundreds of large molecules due to the high computational cost of such simulations. Rule-based modeling is a method that can be used to simulate these processes with reasonably low computational cost, but traditional rule-based modeling approaches do not include details of molecular geometry. The incorporation of geometry into biochemical models can more accurately capture details of these processes, and may lead to insights into how geometry affects the products that form. Furthermore, geometric rule-based modeling can be used to complement other computational methods that explicitly represent molecular geometry in order to quantify binding site accessibility and steric effects.We propose a novel implementation of rule-based modeling that encodes details of molecular geometry into the rules and binding rates. We demonstrate how rules are constructed according to the molecular curvature. We then perform a study of antigen-antibody aggregation using our proposed method. We simulate the binding of antibody complexes to binding regions of the shrimp allergen Pen a 1 using a previously developed 3D rigid-body Monte Carlo simulation, and we analyze the aggregate sizes. Then, using our novel approach, we optimize a rule-based model according to the geometry of the Pen a 1 molecule and the data from the Monte Carlo simulation. We use the distances between the binding regions of Pen a 1 to optimize the rules and binding rates. We perform this procedure for multiple conformations of Pen a 1 and analyze the impact of conformation and resolution on the optimal rule-based model.We find that the optimized rule-based models provide information about the average steric hindrance between binding regions and the probability that antibodies will bind to these regions. These optimized models quantify the variation in aggregate size that results from differences in molecular geometry and from model resolution.

SUBMITTER: Hoard B

PROVIDER: S-EPMC4977479 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Extending rule-based methods to model molecular geometry and 3D model resolution.

Hoard Brittany B Jacobson Bruna B Manavi Kasra K Tapia Lydia L

BMC systems biology 20160801

<h4>Background</h4>Computational modeling is an important tool for the study of complex biochemical processes associated with cell signaling networks. However, it is challenging to simulate processes that involve hundreds of large molecules due to the high computational cost of such simulations. Rule-based modeling is a method that can be used to simulate these processes with reasonably low computational cost, but traditional rule-based modeling approaches do not include details of molecular geo ...[more]

PMID: 27490268

Similar Datasets

Project description:Solvation is of fundamental importance to biomolecular systems. Implicit solvent models, particularly those based on the Poisson-Boltzmann equation for electrostatic analysis, are established approaches for solvation analysis. However, ad hoc solvent-solute interfaces are commonly used in the implicit solvent theory. Recently, we have introduced differential geometry based solvation models which allow the solvent-solute interface to be determined by the variation of a total free energy functional. Atomic fixed partial charges (point charges) are used in our earlier models, which depends on existing molecular mechanical force field software packages for partial charge assignments. As most force field models are parameterized for a certain class of molecules or materials, the use of partial charges limits the accuracy and applicability of our earlier models. Moreover, fixed partial charges do not account for the charge rearrangement during the solvation process. The present work proposes a differential geometry based multiscale solvation model which makes use of the electron density computed directly from the quantum mechanical principle. To this end, we construct a new multiscale total energy functional which consists of not only polar and nonpolar solvation contributions, but also the electronic kinetic and potential energies. By using the Euler-Lagrange variation, we derive a system of three coupled governing equations, i.e., the generalized Poisson-Boltzmann equation for the electrostatic potential, the generalized Laplace-Beltrami equation for the solvent-solute boundary, and the Kohn-Sham equations for the electronic structure. We develop an iterative procedure to solve three coupled equations and to minimize the solvation free energy. The present multiscale model is numerically validated for its stability, consistency and accuracy, and is applied to a few sets of molecules, including a case which is difficult for existing solvation models. Comparison is made to many other classic and quantum models. By using experimental data, we show that the present quantum formulation of our differential geometry based multiscale solvation model improves the prediction of our earlier models, and outperforms some explicit solvation model.

Project description:Objective. Model based deep learning (MBDL) has been challenging to apply to the reconstruction of 3D non-Cartesian MRI due to GPU memory demand because the entire volume is needed for data-consistency steps embedded in the model. This requirement makes holding even a single unroll in GPU memory difficult meaning memory efficient techniques used to increase unroll number like gradient checkpointing and deep equilibrium learning will not work well for high spatial resolution 3D non-Cartesian reconstructions without modification. Here we develop a memory efficient method called block-wise learning that combines gradient checkpointing with patch-wise training to overcome this obstacle and allow for fast and high-quality 3D non-Cartesian reconstructions using MBDL.Approach. Block-wise learning applied to a single unroll decomposes the input volume into smaller patches, gradient checkpoints each patch, passes each patch iteratively through a neural network regularizer, and then rebuilds the full volume from these output patches for data-consistency. This method is applied across unrolls during training. Block-wise learning significantly reduces memory requirements by tying GPU memory for a single unroll to user selected patch size instead of the full volume. This algorithm was used to train a MBDL architecture to reconstruct highly undersampled, 1.25 mm isotropic, pulmonary magnetic resonance angiography volumes with matrix sizes varying from 300-450 × 200-300 × 300-450 on a single GPU. We compared block-wise learning reconstructions against L1 wavelet compressed reconstructions and proxy ground truth images.Main results. MBDL with block-wise learning significantly improved image quality relative to L1 wavelet compressed sensing while simultaneously reducing average reconstruction time 38x.Significance. Block-wise learning allows for MBDL to be applied to high spatial resolution, 3D non-Cartesian datasets with improved image quality and significant reductions in reconstruction time relative to traditional iterative methods.

Dataset Information

Extending rule-based methods to model molecular geometry and 3D model resolution.

Publications

Extending rule-based methods to model molecular geometry and 3D model resolution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets