10 research outputs found
Rapid Sampling of Molecular Motions with Prior Information Constraints
Proteins are active, flexible machines that perform a range of different
functions. Innovative experimental approaches may now provide limited partial
information about conformational changes along motion pathways of proteins.
There is therefore a need for computational approaches that can efficiently
incorporate prior information into motion prediction schemes. In this paper, we
present PathRover, a general setup designed for the integration
of prior information into the motion planning algorithm of rapidly exploring
random trees (RRT). Each suggested motion pathway comprises a sequence of
low-energy clash-free conformations that satisfy an arbitrary number of prior
information constraints. These constraints can be derived from experimental data
or from expert intuition about the motion. The incorporation of prior
information is very straightforward and significantly narrows down the vast
search in the typically high-dimensional conformational space, leading to
dramatic reduction in running time. To allow the use of state-of-the-art energy
functions and conformational sampling, we have integrated this framework into
Rosetta, an accurate protocol for diverse types of structural modeling. The
suggested framework can serve as an effective complementary tool for molecular
dynamics, Normal Mode Analysis, and other prevalent techniques for predicting
motion in proteins. We applied our framework to three different model systems.
We show that a limited set of experimentally motivated constraints may
effectively bias the simulations toward diverse predicates in an outright
fashion, from distance constraints to enforcement of loop closure. In
particular, our analysis sheds light on mechanisms of protein domain swapping
and on the role of different residues in the motion
Low-Pathogenic Avian Influenza Viruses in Wild House Mice
Background: Avian influenza viruses are known to productively infect a number of mammal species, several of which are commonly found on or near poultry and gamebird farms. While control of rodent species is often used to limit avian influenza virus transmission within and among outbreak sites, few studies have investigated the potential role of these species in outbreak dynamics.
Methodology/Principal Findings: We trapped and sampled synanthropic mammals on a gamebird farm in Idaho, USA that had recently experienced a low pathogenic avian influenza outbreak. Six of six house mice (Mus musculus) caught on the outbreak farm were presumptively positive for antibodies to type A influenza. Consequently, we experimentally infected groups of naĂŻve wild-caught house mice with five different low pathogenic avian influenza viruses that included three viruses derived from wild birds and two viruses derived from chickens. Virus replication was efficient in house mice inoculated with viruses derived from wild birds and more moderate for chicken-derived viruses. Mean titers (EID50 equivalents/mL) across all lung samples from seven days of sampling (three mice/day) ranged from 103.89 (H3N6) to 105.06 (H4N6) for the wild bird viruses and 102.08 (H6N2) to 102.85 (H4N8) for the chicken-derived viruses. Interestingly, multiple regression models indicated differential replication between sexes, with significantly (p\u3c0.05) higher concentrations of avian influenza RNA found in females compared with males.
Conclusions/Significance: Avian influenza viruses replicated efficiently in wild-caught house mice without adaptation, indicating mice may be a risk pathway for movement of avian influenza viruses on poultry and gamebird farms. Differential virus replication between males and females warrants further investigation to determine the generality of this result in avian influenza disease dynamics
Searching for Recursively Defined Generic Chemical Patterns in Nonenumerated Fragment Spaces
Retrieving molecules with specific
structural features is a fundamental
requirement of today’s molecular database technologies. Estimates
claim the chemical space relevant for drug discovery to be around
10<sup>60</sup> molecules. This figure is many orders of magnitude
larger than the amount of molecules conventional databases retain
today and will store in the future. An elegant description of such
a large chemical space is provided by the concept of fragment spaces.
A fragment space comprises fragments that are molecules with open
valences and describes rules how to connect these fragments to products.
Due to the combinatorial nature of fragment spaces, a complete enumeration
of its products is intractable. We present an algorithm to search
fragment spaces for generic chemical patterns as present in the SMARTS
chemical pattern language. Our method allows specification of the
chemical surrounding of an atom in a query and, therefore, enables
a chemically intuitive search. During the search, the costly enumeration
of products is avoided. The result is a fragment space that exactly
describes all possible molecules that contain the user-defined pattern.
We evaluated the algorithm in three different drug development use-cases
and performed a large scale statistical analysis with 738 SMARTS patterns
on three public available fragment spaces. Our results show the ability
of the algorithm to explore the chemical space around known active
molecules, to analyze fragment spaces for the presence of likely toxic
molecules, and to identify complex macromolecular structures under
additional structural constraints. By searching the fragment space
in its nonenumerated form, spaces covering up to 10<sup>19</sup> molecules
can be examined in times ranging between 47 s and 19 min depending
on the complexity of the query pattern
Fast Protein Binding Site Comparison via an Index-Based Screening Technology
We present TrixP, a new index-based method for fast protein
binding site comparison and function prediction. TrixP determines
binding site similarities based on the comparison of descriptors that
encode pharmacophoric and spatial features. Therefore, it adopts the
efficient core components of TrixX, a structure-based virtual screening
technology for large compound libraries. TrixP expands this technology
by new components in order to allow a screening of protein libraries.
TrixP accounts for the inherent flexibility of proteins employing
a partial shape matching routine. After the identification of structures
with matching pharmacophoric features and geometric shape, TrixP superimposes
the binding sites and, finally, assesses their similarity according
to the fit of pharmacophoric properties. TrixP is able to find analogies
between closely and distantly related binding sites. Recovery rates
of 81.8% for similar binding site pairs, assisted by rejecting rates
of 99.5% for dissimilar pairs on a test data set containing 1331 pairs,
confirm this ability. TrixP exclusively identifies members of the
same protein family on top ranking positions out of a library consisting
of 9802 binding sites. Furthermore, 30 predicted kinase binding sites
can almost perfectly be classified into their known subfamilies