24 research outputs found
The path of DNA in the kinetochore
The kinetochore is the protein-DNA complex at eukaryotic centromeres that functions as the attachment site for spindle microtubules. In budding yeast, the centromere spans 120 bp, there is a single microtubule per kinetochore, and the entire spindle is composed of 16 kinetochore microtubules plus four interpolar microtubules from each pole. There are >65 different proteins at the kinetochore, organized in at least six core multimeric complexes. A spindle checkpoint network monitors the state of attachment and tension between the microtubule and chromosome. We present a model for the path of DNA in the kinetochore
Dynamic Docking of Conformationally Constrained Macrocycles: Methods and Applications
Many natural products consist of large and flexible macrocycles that engage their targets via multiple contact points. This combination of contained flexibility and large contact area often allows natural products to bind at target surfaces rather than deep pockets, making them attractive scaffolds for inhibiting protein-protein interactions and other challenging therapeutic targets. The increasing ability to manipulate such compounds either biosynthetically or via semisynthetic modification means that these compounds can now be considered as starting points for medchem campaigns rather than solely as ends. Modern medchem benefits substantially from rational improvements made on the basis of molecular docking. As such, docking methods have been enhanced in recent years to deal with the complicated binding modalities and flexible scaffolds of macrocyclic natural products and natural product-like structures. Here, we comprehensively review methods for treating and docking these large macrocyclic scaffolds and discuss some of the resulting advances in medicinal chemistry
Glassy behavior of a homopolymer from molecular dynamics simulations
We study at- and out-of-equilibrium dynamics of a single homopolymer chain at
low temperature using molecular dynamics simulations. The main quantities of
interest are the average root mean square displacement of the monomers below
the theta point, and the structure factor, as a function of time. The
observation of these quantities show a close resemblance to those measured in
structural glasses and suggest that the polymer chain in its low temperature
phase is in a glassy phase, with its dynamics dominated by traps. In
equilibrium, at low temperature, we observe the trapping of the monomers and a
slowing down of the overall motion of the polymer as well as non-exponential
relaxation of the structure factor. In out-of-equilibrium, at low temperatures,
we compute the two-time quantities and observe breaking of ergodicity in a
range of waiting times, with the onset of aging.Comment: 11 pages, 4 figure
Primary Sequences of Protein-Like Copolymers: Levy Flight Type Long Range Correlations
We consider the statistical properties of primary sequences of two-letter HP
copolymers (H for hydrophobic and P for polar) designed to have water soluble
globular conformations with H monomers shielded from water inside the shell of
P monomers. We show, both by computer simulations and by exact analytical
calculation, that for large globules and flexible polymers such sequences
exhibit long-range correlations which can be described by Levy-flight
statistics.Comment: 4 pages, including 2 figures; several references added, some
formulations improve
Interacting Growth Walk - a model for hyperquenched homopolymer glass?
We show that the compact self avoiding walk configurations, kinetically
generated by the recently introduced Interacting Growth Walk (IGW) model, can
be considered as members of a canonical ensemble if they are assigned random
values of energy. Such a mapping is necessary for studying the thermodynamic
behaviour of this system. We have presented the specific heat data for the IGW,
obtained from extensive simulations on a square lattice; we observe a broad
hump in the specific heat above the -point, contrary to expectation.Comment: 4 figures; Submitted to PR
Discrete molecular dynamics simulations of peptide aggregation
We study the aggregation of peptides using the discrete molecular dynamics
simulations. At temperatures above the alpha-helix melting temperature of a
single peptide, the model peptides aggregate into a multi-layer parallel
beta-sheet structure. This structure has an inter-strand distance of 0.48 nm
and an inter-sheet distance of 1.0 nm, which agree with experimental
observations. In this model, the hydrogen bond interactions give rise to the
inter-strand spacing in beta-sheets, while the Go interactions among side
chains make beta-strands parallel to each other and allow beta-sheets to pack
into layers. The aggregates also contain free edges which may allow for further
aggregation of model peptides to form elongated fibrils.Comment: 15 pages, 8 figure
Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
There is still no successful strategy to treat Huntington's disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view of the disease by revealing transcellular transfer of mutated huntingtin proteins which are able to seed oligomers involving wild type forms of the protein. Here we decipher the molecular mechanism of this unconventional heterogeneous oligomerization by performing discrete molecular dynamics simulations. We identify the most probable oligomer conformations and the molecular regions that can be targeted to destabilize them. Our computational findings are complemented experimentally by fluorescence-lifetime imaging microscopy/fluorescence resonance energy transfer (FLIM-FRET) of cells co-transfected with huntingtin proteins containing short and large polyglutamine tracts. Our work clarifies the structural features responsible for heterogeneous huntingtin aggregation with possible implications to contrast the prion-like spreading of Huntington's disease
Computationally Guided Design of Single-Chain Variable Fragment Improves Specificity of Chimeric Antigen Receptors
Chimeric antigen receptor (CAR)-T cell-based immunotherapy of malignant disease relies on the specificity and association constant of single-chain variable fragments (scFvs). The latter are synthesized from parent antibodies by fusing their light (VL) and heavy (VH)-chain variable domains into a single chain using a flexible linker peptide. The fusion of VL and VH domains can distort their relative orientation, thereby compromising specificity and association constant of scFv, and reducing the lytic efficacy of CAR-T cells. Here, we circumvent the complications of domains’ fusion by designing scFv mutants that stabilize interaction between scFv and its target, thereby rescuing scFv efficacy. We employ an iterative approach, based on structural modeling and mutagenesis driven by computational protein design. To demonstrate the power of this approach, we use the scFv derived from an antibody specific to a human leukocyte antigen A2 (HLA-A2)-HER2-derived peptide complex. Whereas the parental antibody is highly specific to its target, the scFv showed reduced specificity. Using our approach, we design mutations into scFvs that restore specificity of the original antibody
Traveling length and minimal traveling time for flow through percolation networks with long-range spatial correlations
We study the distributions of traveling length l and minimal traveling time t
through two-dimensional percolation porous media characterized by long-range
spatial correlations. We model the dynamics of fluid displacement by the
convective movement of tracer particles driven by a pressure difference between
two fixed sites (''wells'') separated by Euclidean distance r. For strongly
correlated pore networks at criticality, we find that the probability
distribution functions P(l) and P(t) follow the same scaling Ansatz originally
proposed for the uncorrelated case, but with quite different scaling exponents.
We relate these changes in dynamical behavior to the main morphological
difference between correlated and uncorrelated clusters, namely, the
compactness of their backbones. Our simulations reveal that the dynamical
scaling exponents for correlated geometries take values intermediate between
the uncorrelated and homogeneous limiting cases
Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon
Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target