Improving of the accuracy and efficiency of implicit solvent models in Biomolecular Modeling
Abstract
Biomolecular Modeling is playing an important role in many practical applications such
as biotechnology and structure-based drug design. One of the essential requirements of
Biomolecular modeling is an accurate description of the solvent (water). The challenge is
to make this description computationally facile that is reasonably fast, simple, robust and
easy to incorporate into existing software packages. The most rigorous procedure to model
the effect of aqueous solvent is to explicitly model every water molecule in the system. For
many practical applications, this approach is computationally too intense, as the number of
required water atoms is on average one order of magnitude larger than the number of atoms
of the molecule of interest.
Implicit solvent models, in which solvent molecules are represented by a continuum function,
have become a popular alternative to explicit solvent methods as they are computationally
more efficient. The Generalized Born (GB) implicit solvent has become quite popular due
to its relative simplicity and computational efficiency. However, recent studies showed serious
deficiencies of many GB variants when applied to Biomolecular Modeling such as an over-
stabilization of alpha helical secondary structures and salt bridges.
In this dissertation we present two new GB models aimed at computing solvation properties
with a reasonable compromise between accuracy and speed. The first GB model, called
NSR6, is based on a numerically surface integration over the standard molecular surface.
When applied to a set of small drug-like molecules, NSR6 produced an accuracy, with respect
to experiments, that is essentially at the same level as that of the expensive explicit solvent
treatment. Furthermore, we developed an analytic GB model, called AR6, based on an
approximation of the volume integral over the standard molecular volume. The accuracy of
the AR6 model is tested relative to the numerically exact NSR6. Overall AR6 produces a
good accuracy and is suitable for Molecular Dynamics simulations which is the main intended
application.
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- Doctoral Dissertations [14868]