Analysis of macromolecular/small-molecule
binding pockets can provide
important insights into molecular recognition and receptor dynamics.
Since its release in 2011, the POVME (POcket Volume MEasurer) algorithm
has been widely adopted as a simple-to-use tool for measuring and
characterizing pocket volumes and shapes. We here present POVME 2.0,
which is an order of magnitude faster, has improved accuracy, includes
a graphical user interface, and can produce volumetric density maps
for improved pocket analysis. To demonstrate the utility of the algorithm,
we use it to analyze the binding pocket of RNA editing ligase 1 from
the unicellular parasite Trypanosoma brucei, the
etiological agent of African sleeping sickness. The POVME analysis
characterizes the full dynamics of a potentially druggable transient
binding pocket and so may guide future antitrypanosomal drug-discovery
efforts. We are hopeful that this new version will be a useful tool
for the computational- and medicinal-chemist community.
Allostery
can occur by way of subtle cooperation among protein
residues (e.g., amino acids) even in the absence of large conformational
shifts. Dynamical network analysis has been used to model this cooperation,
helping to computationally explain how binding to an allosteric site
can impact the behavior of a primary site many ångstroms away.
Traditionally, computational efforts have focused on the most optimal
path of correlated motions leading from the allosteric to the primary
active site. We present a program called Weighted Implementation of
Suboptimal Paths (WISP) capable of rapidly identifying additional
suboptimal pathways that may also play important roles in the transmission
of allosteric signals. Aside from providing signal redundancy, suboptimal
paths traverse residues that, if disrupted through pharmacological
or mutational means, could modulate the allosteric regulation of important
drug targets. To demonstrate the utility of our program, we present
a case study describing the allostery of HisH-HisF, an amidotransferase
from T. maritima thermotiga. WISP and
its VMD-based graphical user interface (GUI) can be downloaded from .
We present the Simulation Enabled Estimation of Kinetic Rates (SEEKR) package, a suite of open-source scripts and tools designed to enable researchers to perform multi-scale computation of the kinetics of molecular binding, unbinding, and transport using a combination of molecular dynamics, Brownian dynamics, and milestoning theory. To demonstrate its utility, we compute the kon, koff, and ΔGbind for the protein trypsin with its noncovalent binder, benzamidine, and examine the kinetics and other results generated in the context of the new software, and compare our findings to previous studies performed on the same system. We compute a kon estimate of 2.1±0.3•107 M−1s−1, a koff estimate of 83±14 s−1, and a ΔGbind of −7.4±0.2 kcal•mol−1, all of which compare closely to the experimentally measured values of 2.9•107 M−1s−1, 600±300 s−1, and −6.7 kcal•mol−1, respectively.
The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 μs of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.
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