PNNL-13501 - Pacific Northwest National Laboratory

HostBuilder: A Tool for the Combinatorial Generation of Host Molecules
Study Control Number: PN00051/1458
Benjamin P. Hay
Host molecules that selectively complex targeted guests have potential broad application to problems currently
challenging DOE including detection of species in groundwater and chemical process streams; the separation and
concentration of radionuclides and other ionic species from nuclear waste, contaminated soils, and groundwater; and the
encapsulation of radionuclides in medical applications. Motivated by the expense of host development in the laboratory,
we are creating software to evaluate large numbers of possible host architectures and rapidly identify the best candidates
prior to synthesis and testing.
Project Description
The purpose of this project is to create software for rapid
discovery of new host architectures. The approach
involves a combinatorial method in which we examine
every possible architecture for a set of donor groups. In
the first year of the project, we developed and coded an
algorithm for connecting two host fragments to form
candidate structures and to rank-order the results with
respect to the best fit to a guest. In addition, we
constructed a comprehensive link library derived from
small alkane and alkene fragments. Tests demonstrate
that the algorithm is computationally very efficient and
with recent hardware we estimate that speeds in excess of
one million host molecules per second will be attainable.
Code development remains in progress and a final version
of the software will be completed in 2001.
Introduction
Many fundamental studies of host-guest interactions have
been performed. Effective computational methods are
available for ranking proposed host structures in terms of
their binding affinities for specific guests on a case-bycase
basis. However, no effective method exists for
computer-aided design of new and improved host
molecules. What is missing is an efficient and systematic
means of generating trial structures. To fill this gap, we
are working to develop a code, HostBuilder, that will be
capable of generating and rank-ordering millions of
possible host architectures from a given set of donor
groups. This new capability will provide DOE with an
alternative to expensive Edisonian experimentation that
currently dominates host-development research.
The objective is to develop a computational approach for
discovering new host molecule structures with the
potential to tightly bind to a specified guest. To achieve
130 FY 2000 Laboratory Directed Research and Development Annual Report
this goal, we are combining fundamental knowledge of
guest-donor group interactions with a combinatorial
geometric structure generator to produce and rank a large
library of possible host structures. The project has two
distinct tasks: 1) developing and encoding the algorithms
for the combinatorial geometric structure generator,
HostBuilder; and 2) constructing a large database of
linking groups. Our efforts focused on the first task with
the development of a prototype version of the HostBuilder
program. Our future objective will be the improvement of
the HostBuilder program, completion of a larger linker
database, and validation of the final version of the
software. The successful completion of this project will
yield a powerful software package to guide the
development of molecular and ion recognition agents. To
our knowledge, this capability currently does not exist
elsewhere.
Results and Accomplishments
We successfully completed a prototype version of the
HostBuilder code. This code, which consists of
8,500 lines of standard FORTRAN, takes two host
fragments and builds every possible architecture that can
be made by connecting the fragments to linkage structures
taken from a database. By examining all rotamers and
enantiomers, all possible configurations of each molecular
connectivity were considered during the building process.
After construction, each candidate host architecture was
rank-ordered with respect to guest complementarity based
upon knowledge of the optimal coordination geometry of
each donor group. After all candidates were evaluated,
the best structures were written to a graphics file for
viewing. The current linker database contains molecular
fragments representing all possible connectivities that can
be formed from alkanes and alkenes containing four
carbon atoms or less.