College of Liberal Arts & Sciences
Subscribe to Recent Comp Bio Pubs feed Recent Comp Bio Pubs
NCBI: db=pubmed; Term=(Vakser, Ilya[Author]) OR ((Miao, Yinglong[Author]) AND Kansas) OR (Deeds, Eric[Author]) OR (Ray, Christian[Author]) OR (Slusky, Joanna[Author]) OR (Ray JC[Author] AND Kansas)
Updated: 58 min 21 sec ago

Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor.

Tue, 08/07/2018 - 06:55
Related Articles

Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor.

Proc Natl Acad Sci U S A. 2018 03 20;115(12):3036-3041

Authors: Miao Y, McCammon JA

Abstract
Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 Å in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions.

PMID: 29507218 [PubMed - indexed for MEDLINE]

Efflux Pumps Represent Possible Evolutionary Convergence onto the β-Barrel Fold.

Tue, 07/31/2018 - 05:33
Related Articles

Efflux Pumps Represent Possible Evolutionary Convergence onto the β-Barrel Fold.

Structure. 2018 Jul 05;:

Authors: Franklin MW, Nepomnyachiy S, Feehan R, Ben-Tal N, Kolodny R, Slusky JSG

Abstract
There are around 100 varieties of outer membrane proteins in each Gram-negative bacteria. All of these proteins have the same fold-an up-down β-barrel. It has been suggested that all membrane β-barrels excluding lysins are homologous. Here we suggest that β-barrels of efflux pumps have converged on this fold as well. By grouping structurally solved outer membrane β-barrels (OMBBs) by sequence we find that the membrane environment may have led to convergent evolution of the barrel fold. Specifically, the lack of sequence linkage to other barrels coupled with distinctive structural differences, such as differences in strand tilt and barrel radius, suggest that the outer membrane factor of efflux pumps evolutionarily converged on the barrel. Rather than being related to other OMBBs, sequence and structural similarity in the periplasmic region of the outer membrane factor of efflux pumps suggests an evolutionary link to the periplasmic subunit of the same pump complex.

PMID: 30057025 [PubMed - as supplied by publisher]

Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking.

Sat, 07/14/2018 - 07:07
Related Articles

Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking.

J Comput Aided Mol Des. 2018 Jul 12;:

Authors: Belkin S, Kundrotas PJ, Vakser IA

Abstract
Modulating protein interaction pathways may lead to the cure of many diseases. Known protein-protein inhibitors bind to large pockets on the protein-protein interface. Such large pockets are detected also in the protein-protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized protein-protein complex as a starting point for drug design.

PMID: 30003468 [PubMed - as supplied by publisher]

Tight Turns of Outer Membrane Proteins: An Analysis of Sequence, Structure, and Hydrogen Bonding.

Wed, 06/27/2018 - 07:46

Tight Turns of Outer Membrane Proteins: An Analysis of Sequence, Structure, and Hydrogen Bonding.

J Mol Biol. 2018 Jun 23;:

Authors: Franklin MW, Slusky JSG

Abstract
As a structural class, tight turns can control molecular recognition, enzymatic activity, and nucleation of folding. They have been extensively characterized in soluble proteins but have not been characterized in outer membrane proteins (OMPs), where they also support critical functions. We clustered the 4-6 residue tight turns of 110 OMPs to characterize the phi/psi angles, sequence, and hydrogen bonding of these structures. We find significant differences between reports of soluble protein tight turns and OMP tight turns. Since OMP strands are less twisted than soluble strands they favor different turn structures types. Moreover, the membrane localization of OMPs yields different sequence hallmarks for their tight turns relative to soluble protein turns. We also characterize the differences in phi/psi angles, sequence, and hydrogen bonding between OMP extracellular loops and OMP periplasmic turns. As previously noted, the extracellular loops tend to be much longer than the periplasmic turns. We find that this difference in length is due to the broader distribution of lengths of the extracellular loops not a large difference in the median length. Extracellular loops also tend to have more charged residues as predicted by the charge-out rule. Finally, in all OMP tight turns, hydrogen bonding between the sidechain and backbone two to four residues away from that side chain plays an important role. These bonds preferentially use an Asp, Asn, Ser or Thr residue in a beta or pro phi/psi conformation. We anticipate that this study will be applicable to future design and structure prediction of OMPs.

PMID: 29944853 [PubMed - as supplied by publisher]


One of 34 U.S. public institutions in the prestigious Association of American Universities
44 nationally ranked graduate programs.
—U.S. News & World Report
Top 50 nationwide for size of library collection.
—ALA
23rd nationwide for service to veterans —"Best for Vets," Military Times
KU Today