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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)
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Identification of SLAC1 anion channel residues required for CO2/bicarbonate sensing and regulation of stomatal movements.

Fri, 10/12/2018 - 05:59
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Identification of SLAC1 anion channel residues required for CO2/bicarbonate sensing and regulation of stomatal movements.

Proc Natl Acad Sci U S A. 2018 Oct 09;:

Authors: Zhang J, Wang N, Miao Y, Hauser F, McCammon JA, Rappel WJ, Schroeder JI

Abstract
Increases in CO2 concentration in plant leaves due to respiration in the dark and the continuing atmospheric [CO2] rise cause closing of stomatal pores, thus affecting plant-water relations globally. However, the underlying CO2/bicarbonate (CO2/HCO3 -) sensing mechanisms remain unknown. [CO2] elevation in leaves triggers stomatal closure by anion efflux mediated via the SLAC1 anion channel localized in the plasma membrane of guard cells. Previous reconstitution analysis has suggested that intracellular bicarbonate ions might directly up-regulate SLAC1 channel activity. However, whether such a CO2/HCO3 - regulation of SLAC1 is relevant for CO2 control of stomatal movements in planta remains unknown. Here, we computationally probe for candidate bicarbonate-interacting sites within the SLAC1 anion channel via long-timescale Gaussian accelerated molecular dynamics (GaMD) simulations. Mutations of two putative bicarbonate-interacting residues, R256 and R321, impaired the enhancement of the SLAC1 anion channel activity by CO2/HCO3 - in Xenopus oocytes. Mutations of the neighboring charged amino acid K255 and residue R432 and the predicted gate residue F450 did not affect HCO3 - regulation of SLAC1. Notably, gas-exchange experiments with slac1-transformed plants expressing mutated SLAC1 proteins revealed that the SLAC1 residue R256 is required for CO2 regulation of stomatal movements in planta, but not for abscisic acid (ABA)-induced stomatal closing. Patch clamp analyses of guard cells show that activation of S-type anion channels by CO2/HCO3 -, but not by ABA, was impaired, indicating the relevance of R256 for CO2 signal transduction. Together, these analyses suggest that the SLAC1 anion channel is one of the physiologically relevant CO2/HCO3 - sensors in guard cells.

PMID: 30301791 [PubMed - as supplied by publisher]

A Computational Modeling Approach Predicts Interaction of the Antifungal Protein AFP from Aspergillus giganteus with Fungal Membranes via Its γ-Core Motif.

Fri, 10/05/2018 - 06:58
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A Computational Modeling Approach Predicts Interaction of the Antifungal Protein AFP from Aspergillus giganteus with Fungal Membranes via Its γ-Core Motif.

mSphere. 2018 Oct 03;3(5):

Authors: Utesch T, de Miguel Catalina A, Schattenberg C, Paege N, Schmieder P, Krause E, Miao Y, McCammon JA, Meyer V, Jung S, Mroginski MA

Abstract
Fungal pathogens kill more people per year globally than malaria or tuberculosis and threaten international food security through crop destruction. New sophisticated strategies to inhibit fungal growth are thus urgently needed. Among the potential candidate molecules that strongly inhibit fungal spore germination are small cationic, cysteine-stabilized proteins of the AFP family secreted by a group of filamentous Ascomycetes. Its founding member, AFP from Aspergillus giganteus, is of particular interest since it selectively inhibits the growth of filamentous fungi without affecting the viability of mammalian, plant, or bacterial cells. AFPs are also characterized by their high efficacy and stability. Thus, AFP can serve as a lead compound for the development of novel antifungals. Notably, all members of the AFP family comprise a γ-core motif which is conserved in all antimicrobial proteins from pro- and eukaryotes and known to interfere with the integrity of cytoplasmic plasma membranes. In this study, we used classical molecular dynamics simulations combined with wet laboratory experiments and nuclear magnetic resonance (NMR) spectroscopy to characterize the structure and dynamical behavior of AFP isomers in solution and their interaction with fungal model membranes. We demonstrate that the γ-core motif of structurally conserved AFP is the key for its membrane interaction, thus verifying for the first time that the conserved γ-core motif of antimicrobial proteins is directly involved in protein-membrane interactions. Furthermore, molecular dynamic simulations suggested that AFP does not destroy the fungal membrane by pore formation but covers its surface in a well-defined manner, using a multistep mechanism to destroy the membranes integrity.IMPORTANCE Fungal pathogens pose a serious danger to human welfare since they kill more people per year than malaria or tuberculosis and are responsible for crop losses worldwide. The treatment of fungal infections is becoming more complicated as fungi develop resistances against commonly used fungicides. Therefore, discovery and development of novel antifungal agents are of utmost importance.

PMID: 30282755 [PubMed - in process]

Computational Feasibility of an Exhaustive Search of Side-Chain Conformations in Protein-Protein Docking.

Wed, 09/19/2018 - 06:23
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Computational Feasibility of an Exhaustive Search of Side-Chain Conformations in Protein-Protein Docking.

J Comput Chem. 2018 Sep 18;:

Authors: Dauzhenka T, Kundrotas PJ, Vakser IA

Abstract
Protein-protein docking procedures typically perform the global scan of the proteins relative positions, followed by the local refinement of the putative matches. Because of the size of the search space, the global scan is usually implemented as rigid-body search, using computationally inexpensive intermolecular energy approximations. An adequate refinement has to take into account structural flexibility. Since the refinement performs conformational search of the interacting proteins, it is extremely computationally challenging, given the enormous amount of the internal degrees of freedom. Different approaches limit the search space by restricting the search to the side chains, rotameric states, coarse-grained structure representation, principal normal modes, and so on. Still, even with the approximations, the refinement presents an extreme computational challenge due to the very large number of the remaining degrees of freedom. Given the complexity of the search space, the advantage of the exhaustive search is obvious. The obstacle to such search is computational feasibility. However, the growing computational power of modern computers, especially due to the increasing utilization of Graphics Processing Unit (GPU) with large amount of specialized computing cores, extends the ranges of applicability of the brute-force search methods. This proof-of-concept study demonstrates computational feasibility of an exhaustive search of side-chain conformations in protein pocking. The procedure, implemented on the GPU architecture, was used to generate the optimal conformations in a large representative set of protein-protein complexes. © 2018 Wiley Periodicals, Inc.

PMID: 30226647 [PubMed - as supplied by publisher]

Acceleration of biomolecular kinetics in Gaussian accelerated molecular dynamics.

Fri, 08/24/2018 - 08:31
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Acceleration of biomolecular kinetics in Gaussian accelerated molecular dynamics.

J Chem Phys. 2018 Aug 21;149(7):072308

Authors: Miao Y

Abstract
Recent studies demonstrated that Gaussian accelerated molecular dynamics (GaMD) is a robust computational technique, which provides simultaneous unconstrained enhanced sampling and free energy calculations of biomolecules. However, the exact acceleration of biomolecular dynamics or speedup of kinetic rates in GaMD simulations and, more broadly, in enhanced sampling methods, remains a challenging task to be determined. Here, the GaMD acceleration is examined using alanine dipeptide in explicit solvent as a biomolecular model system. Relative to long conventional molecular dynamics simulation, GaMD simulations exhibited ∼36-67 times speedup for sampling of the backbone dihedral transitions. The acceleration depended on level of the GaMD boost potential. Furthermore, Kramers' rate theory was applied to estimate GaMD acceleration using simulation-derived diffusion coefficients, curvatures and barriers of free energy profiles. In most cases, the calculations also showed significant speedup of dihedral transitions in GaMD, although the GaMD acceleration factors tended to be underestimated by ∼3-96 fold. Because greater boost potential can be applied in GaMD simulations of systems with increased sizes, which potentially leads to higher acceleration, it is subject to future studies on accelerating the dynamics and recovering kinetic rates of larger biomolecules such as proteins and protein-protein/nucleic acid complexes.

PMID: 30134710 [PubMed - in process]

Lineage space and the propensity of bacterial cells to undergo growth transitions.

Thu, 08/23/2018 - 07:40
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Lineage space and the propensity of bacterial cells to undergo growth transitions.

PLoS Comput Biol. 2018 Aug 22;14(8):e1006380

Authors: Bandyopadhyay A, Wang H, Ray JCJ

Abstract
The molecular makeup of the offspring of a dividing cell gradually becomes phenotypically decorrelated from the parent cell by noise and regulatory mechanisms that amplify phenotypic heterogeneity. Such regulatory mechanisms form networks that contain thresholds between phenotypes. Populations of cells can be poised near the threshold so that a subset of the population probabilistically undergoes the phenotypic transition. We sought to characterize the diversity of bacterial populations around a growth-modulating threshold via analysis of the effect of non-genetic inheritance, similar to conditions that create antibiotic-tolerant persister cells and other examples of bet hedging. Using simulations and experimental lineage data in Escherichia coli, we present evidence that regulation of growth amplifies the dependence of growth arrest on cellular lineage, causing clusters of related cells undergo growth arrest in certain conditions. Our simulations predict that lineage correlations and the sensitivity of growth to changes in toxin levels coincide in a critical regime. Below the critical regime, the sizes of related growth arrested clusters are distributed exponentially, while in the critical regime clusters sizes are more likely to become large. Furthermore, phenotypic diversity can be nearly as high as possible near the critical regime, but for most parameter values it falls far below the theoretical limit. We conclude that lineage information is indispensable for understanding regulation of cellular growth.

PMID: 30133447 [PubMed - as supplied by publisher]

Contact Potential for Structure Prediction of Proteins and Protein Complexes from Potts Model.

Tue, 08/21/2018 - 05:28
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Contact Potential for Structure Prediction of Proteins and Protein Complexes from Potts Model.

Biophys J. 2018 Aug 08;:

Authors: Anishchenko I, Kundrotas PJ, Vakser IA

Abstract
The energy function is the key component of protein modeling methodology. This work presents a semianalytical approach to the development of contact potentials for protein structure modeling. Residue-residue and atom-atom contact energies were derived by maximizing the probability of observing native sequences in a nonredundant set of protein structures. The optimization task was formulated as an inverse statistical mechanics problem applied to the Potts model. Its solution by pseudolikelihood maximization provides consistent estimates of coupling constants at atomic and residue levels. The best performance was achieved when interacting atoms were grouped according to their physicochemical properties. For individual protein structures, the performance of the contact potentials in distinguishing near-native structures from the decoys is similar to the top-performing scoring functions. The potentials also yielded significant improvement in the protein docking success rates. The potentials recapitulated experimentally determined protein stability changes upon point mutations and protein-protein binding affinities. The approach offers a different perspective on knowledge-based potentials and may serve as the basis for their further development.

PMID: 30122295 [PubMed - as supplied by publisher]

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

Tue, 08/07/2018 - 06:55
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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
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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
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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]


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