444 research outputs found
Efficient numerical algorithms for surface formulations of mathematical models for biomolecule analysis and design
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (p. 179-183).This thesis presents a set of numerical techniques that extend and improve computational modeling approaches for biomolecule analysis and design. The presented research focuses on surface formulations of modeling problems related to the estimation of the energetic cost to transfer a biomolecule from the gas phase to aqueous solution. The thesis discusses four contributions to modeling biomolecular interactions. First, the thesis presents an approach to allow accurate discretization of the most prevalent mathematical definitions of the biomolecule-solvent interface; also presented are a number of accurate techniques for numerically integrating possibly singular functions over the discretized surfaces. Such techniques are essential for solving surface formulations numerically. The second part of the thesis presents a fast multiscale numerical algorithm, FFTSVD, that efficiently solves large boundary-element method problems in biomolecule electrostatics. The algorithm synthesizes elements of other popular fast algorithms to achieve excellent efficiency and flexibility. The third thesis component describes an integral-equation formulation and boundary-element method implementation for biomolecule electrostatic analysis.(cont.) The formulation and implementation allow the solution of complicated molecular topologies and physical models. Furthermore, by applying the methods developed in the first half of the thesis, the implementation can deliver superior accuracy for competitive performance. Finally, the thesis describes a highly efficient numerical method for calculating a biomolecular charge distribution that minimizes the free energy' change of binding to another molecule. The approach, which represents a novel PDE-constrained methodology, builds on well-developed physical theory. Computational results illustrate not only the method's improved performance but also its application to realistic biomolecule problems.by Jaydeep Porter Bardhan.Ph.D
Variational Methods for Biomolecular Modeling
Structure, function and dynamics of many biomolecular systems can be
characterized by the energetic variational principle and the corresponding
systems of partial differential equations (PDEs). This principle allows us to
focus on the identification of essential energetic components, the optimal
parametrization of energies, and the efficient computational implementation of
energy variation or minimization. Given the fact that complex biomolecular
systems are structurally non-uniform and their interactions occur through
contact interfaces, their free energies are associated with various interfaces
as well, such as solute-solvent interface, molecular binding interface, lipid
domain interface, and membrane surfaces. This fact motivates the inclusion of
interface geometry, particular its curvatures, to the parametrization of free
energies. Applications of such interface geometry based energetic variational
principles are illustrated through three concrete topics: the multiscale
modeling of biomolecular electrostatics and solvation that includes the
curvature energy of the molecular surface, the formation of microdomains on
lipid membrane due to the geometric and molecular mechanics at the lipid
interface, and the mean curvature driven protein localization on membrane
surfaces. By further implicitly representing the interface using a phase field
function over the entire domain, one can simulate the dynamics of the interface
and the corresponding energy variation by evolving the phase field function,
achieving significant reduction of the number of degrees of freedom and
computational complexity. Strategies for improving the efficiency of
computational implementations and for extending applications to coarse-graining
or multiscale molecular simulations are outlined.Comment: 36 page
Representability of algebraic topology for biomolecules in machine learning based scoring and virtual screening
This work introduces a number of algebraic topology approaches, such as
multicomponent persistent homology, multi-level persistent homology and
electrostatic persistence for the representation, characterization, and
description of small molecules and biomolecular complexes. Multicomponent
persistent homology retains critical chemical and biological information during
the topological simplification of biomolecular geometric complexity.
Multi-level persistent homology enables a tailored topological description of
inter- and/or intra-molecular interactions of interest. Electrostatic
persistence incorporates partial charge information into topological
invariants. These topological methods are paired with Wasserstein distance to
characterize similarities between molecules and are further integrated with a
variety of machine learning algorithms, including k-nearest neighbors, ensemble
of trees, and deep convolutional neural networks, to manifest their descriptive
and predictive powers for chemical and biological problems. Extensive numerical
experiments involving more than 4,000 protein-ligand complexes from the PDBBind
database and near 100,000 ligands and decoys in the DUD database are performed
to test respectively the scoring power and the virtual screening power of the
proposed topological approaches. It is demonstrated that the present approaches
outperform the modern machine learning based methods in protein-ligand binding
affinity predictions and ligand-decoy discrimination
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