4 research outputs found
Protein loop compaction and the origin of the effect of arginine and glutamic acid mixtures on solubility, stability and transient oligomerization of proteins
Addition of a 50 mM mixture of l-arginine and l-glutamic acid (RE) is extensively used to improve protein solubility and stability, although the origin of the effect is not well understood. We present Small Angle X-ray Scattering (SAXS) and Nuclear Magnetic Resonance (NMR) results showing that RE induces protein compaction by collapsing flexible loops on the protein core. This is suggested to be a general mechanism preventing aggregation and improving resistance to proteases and to originate from the polyelectrolyte nature of RE. Molecular polyelectrolyte mixtures are expected to display long range correlation effects according to dressed interaction site theory. We hypothesize that perturbation of the RE solution by dissolved proteins is proportional to the volume occupied by the protein. As a consequence, loop collapse, minimizing the effective protein volume, is favored in the presence of RE
Individual & Collective Human Intelligence in Drug Design: Evaluating the Search Strategy
In recent years, individual and collective human
intelligence, defined as the knowledge, skills, reasoning and
intuition of individuals and groups, have been used in combination
with computer algorithms to solve complex scientific problems. Such
approach was successfully used in different research fields such as:
structural biology, comparative genomics, macromolecular
crystallography and RNA design. Herein we describe an attempt to use
a similar approach in small-molecule drug discovery, specifically to
drive search strategies of de novo drug design. This
is assessed with a case study that consists
of a series of public experiments in which participants had to
explore the huge chemical space in
silico to
find predefined
compounds
by designing
molecules and analyzing the
score associate with
them. Such
a
process
may
be seen as
an instantaneous surrogate of the
classical
design-make-test cycles carried out by medicinal chemists during the
drug
discovery hit to lead phase but not hindered by long synthesis and
testing times.
The objectives of this case study are to
give the first insights
towards: the assessment of
human intelligence in chemical space exploration problems;
compare the performance of individual and collective human
intelligence in such a problems; and also contrast some human and
artificial
intelligence achievements
in de
novo drug
design.</p
Protein loop compaction and the origin of the effect of arginine and glutamic acid mixtures on solubility, stability and transient oligomerization of proteins
Addition of a 50 mM mixture of l-arginine and l-glutamic acid (RE) is extensively used to improve protein solubility and stability, although the origin of the effect is not well understood. We present Small Angle X-ray Scattering (SAXS) and Nuclear Magnetic Resonance (NMR) results showing that RE induces protein compaction by collapsing flexible loops on the protein core. This is suggested to be a general mechanism preventing aggregation and improving resistance to proteases and to originate from the polyelectrolyte nature of RE. Molecular polyelectrolyte mixtures are expected to display long range correlation effects according to dressed interaction site theory. We hypothesize that perturbation of the RE solution by dissolved proteins is proportional to the volume occupied by the protein. As a consequence, loop collapse, minimizing the effective protein volume, is favored in the presence of RE