Article

# Network-based models as tools hinting at nonevident protein functionality.

• ##### Osman Burak Okan
Faculty of Engineering and Natural Sciences, Sabanci University, 34956 Istanbul, Turkey.
Annual Review of Biophysics (Impact Factor: 12.63). 02/2012; 41:205-25. DOI: 10.1146/annurev-biophys-050511-102305
Source: PubMed

ABSTRACT Network-based models of proteins are popular tools employed to determine dynamic features related to the folded structure. They encompass all topological and geometric computational approaches idealizing proteins as directly interacting nodes. Topology makes use of neighborhood information of residues, and geometry includes relative placement of neighbors. Coarse-grained approaches efficiently predict alternative conformations because of inherent collectivity in the protein structure. Such collectivity is moderated by topological characteristics that also tune neighborhood structure: That rich residues have richer neighbors secures robustness toward random loss of interactions/nodes due to environmental fluctuations/mutations. Geometry conveys the additional information of force balance to network models, establishing the local shape of the energy landscape. Here, residue and/or bond perturbations are critically evaluated to suggest new experiments, as network-based computational techniques prove useful in capturing domain movements and conformational shifts resulting from environmental alterations. Evolutionarily conserved residues are optimally connected, defining a subnetwork that may be utilized for further coarsening.

0 Bookmarks
·
110 Views
• Source
##### Article: Designing molecular dynamics simulations to shift populations of the conformational States of calmodulin.
[Hide abstract]
ABSTRACT: We elucidate the mechanisms that lead to population shifts in the conformational states of calcium-loaded calmodulin (Ca(2+)-CaM). We design extensive molecular dynamics simulations to classify the effects that are responsible for adopting occupied conformations available in the ensemble of NMR structures. Electrostatic interactions amongst the different regions of the protein and with its vicinal water are herein mediated by lowering the ionic strength or the pH. Amino acid E31, which is one of the few charged residues whose ionization state is highly sensitive to pH differences in the physiological range, proves to be distinctive in its control of population shifts. E31A mutation at low ionic strength results in a distinct change from an extended to a compact Ca(2+)-CaM conformation within tens of nanoseconds, that otherwise occur on the time scales of microseconds. The kinked linker found in this particular compact form is observed in many of the target-bound forms of Ca(2+)-CaM, increasing the binding affinity. This mutation is unique in controlling C-lobe dynamics by affecting the fluctuations between the EF-hand motif helices. We also monitor the effect of the ionic strength on the conformational multiplicity of Ca(2+)-CaM. By lowering the ionic strength, the tendency of nonspecific anions in water to accumulate near the protein surface increases, especially in the vicinity of the linker. The change in the distribution of ions in the vicinal layer of water allows N- and C- lobes to span a wide variety of relative orientations that are otherwise not observed at physiological ionic strength. E31 protonation restores the conformations associated with physiological environmental conditions even at low ionic strength.
PLoS Computational Biology 12/2013; 9(12):e1003366. · 4.87 Impact Factor
• Source
##### Article: Effective harmonic potentials: insights into the internal cooperativity and sequence-specificity of protein dynamics.
[Hide abstract]
ABSTRACT: The proper biological functioning of proteins often relies on the occurrence of coordinated fluctuations around their native structure, or on their ability to perform wider and sometimes highly elaborated motions. Hence, there is considerable interest in the definition of accurate coarse-grained descriptions of protein dynamics, as an alternative to more computationally expensive approaches. In particular, the elastic network model, in which residue motions are subjected to pairwise harmonic potentials, is known to capture essential aspects of conformational dynamics in proteins, but has so far remained mostly phenomenological, and unable to account for the chemical specificities of amino acids. We propose, for the first time, a method to derive residue- and distance-specific effective harmonic potentials from the statistical analysis of an extensive dataset of NMR conformational ensembles. These potentials constitute dynamical counterparts to the mean-force statistical potentials commonly used for static analyses of protein structures. In the context of the elastic network model, they yield a strongly improved description of the cooperative aspects of residue motions, and give the opportunity to systematically explore the influence of sequence details on protein dynamics.
PLoS Computational Biology 08/2013; 9(8):e1003209. · 4.87 Impact Factor
• Source
##### Article: Protonation States of Remote Residues Affect Binding-Release Dynamics of the Ligand but not the Conformation of apo Ferric Binding Protein
[Hide abstract]
ABSTRACT: We have studied the apo (Fe3+ free) form of periplasmic ferric binding protein (FbpA) under different conditions and we have monitored the changes in the binding and release dynamics of H2PO4- that acts as a synergistic anion in the presence of Fe3+. Our simulations predict a dissociation constant of 2.2$\pm$0.2 mM which is in remarkable agreement with the experimentally measured value of 2.3$\pm$0.3 mM under the same ionization strength and pH conditions. We apply perturbations relevant for changes in environmental conditions as (i) different values of ionic strength (IS), and (ii) protonation of a group of residues to mimic a different pH environment. Local perturbations are also studied by protonation or mutation of a site distal to the binding region that is known to mechanically manipulate the hinge-like motions of FbpA. We find that while the average conformation of the protein is intact in all simulations, the H2PO4- dynamics may be substantially altered by the changing conditions. In particular, the bound fraction which is 20$\%$ for the wild type system is increased to 50$\%$ with a D52A mutation/protonation and further to over 90$\%$ at the protonation conditions mimicking those at pH 5.5. The change in the dynamics is traced to the altered electrostatic distribution on the surface of the protein which in turn affects hydrogen bonding patterns at the active site. The observations are quantified by rigorous free energy calculations. Our results lend clues as to how the environment versus single residue perturbations may be utilized for regulation of binding modes in hFbpA systems in the absence of conformational changes.
The journal of physical chemistry. B. 02/2014;