Structural, geometric and genetic factors predict interregional brain connectivity patterns probed by electrocorticography.

Electrocorticography (ECoG) data can be used to estimate brain-wide connectivity patterns. Yet, the invasiveness of ECoG, incomplete cortical coverage, and variability in electrode placement across individuals make the network analysis of ECoG data challenging. Here, we show that the architecture of whole-brain ECoG networks and the factors that shape it can be studied by analysing whole-brain, interregional and band-limited ECoG networks from a large cohort-in this case, of individuals with medication-resistant epilepsy. Using tools from network science, we characterized the basic organization of ECoG networks, including frequency-specific architecture, segregated modules and the dependence of connection weights on interregional Euclidean distance. We then used linear models to explain variabilities in the connection strengths between pairs of brain regions, and to highlight the joint role, in shaping the brain-wide organization of ECoG networks, of communication along white matter pathways, interregional Euclidean distance and correlated gene expression. Moreover, we extended these models to predict out-of-sample, single-subject data. Our predictive models may have future clinical utility; for example, by anticipating the effect of cortical resection on interregional communication.

Role of Graph Architecture in Controlling Dynamical Networks with Applications to Neural Systems.

Networked systems display complex patterns of interactions between components. In physical networks, these interactions often occur along structural connections that link components in a hard-wired connection topology, supporting a variety of system-wide dynamical behaviors such as synchronization. While descriptions of these behaviors are important, they are only a first step towards understanding and harnessing the relationship between network topology and system behavior. Here, we use linear network control theory to derive accurate closed-form expressions that relate the connectivity of a subset of structural connections (those linking driver nodes to non-driver nodes) to the minimum energy required to control networked systems. To illustrate the utility of the mathematics, we apply this approach to high-resolution connectomes recently reconstructed from Drosophila, mouse, and human brains. We use these principles to suggest an advantage of the human brain in supporting diverse network dynamics with small energetic costs while remaining robust to perturbations, and to perform clinically accessible targeted manipulation of the brain's control performance by removing single edges in the network. Generally, our results ground the expectation of a control system's behavior in its network architecture, and directly inspire new directions in network analysis and design via distributed control.

Near-exact enthalpy-entropy compensation governs the thermal unfolding of protonation states of oxidized cytochrome c.

This paper reports the first quantitative analysis of the thermal transitions of all protonation states of oxidized horse heart cytochrome c at low anion concentration. Changes of secondary and tertiary structure were probed by ultraviolet (UV) as well as visible circular dichroism and absorption spectroscopy, respectively. The temperature dependence of spectra were recorded at pH values assignable to a set of different protonation states which encompass the canonical Theorell-Åkesson states and the recently discovered III* state. Our experimental data suggest a two-step process of thermal unfolding for all protonation states. The respective thermodynamic parameters were obtained from a global analysis of the temperature dependence of corresponding visible circular dichroism (CD) and absorption spectra. The results of this analysis revealed a statistically significant enthalpy-entropy compensation with different apparent compensation temperatures for the two consecutive thermal transitions (319 and 357 K). This reflects the narrow distribution of the respective folding temperatures. UVCD spectra suggest that even the thermal transitions of protonation states occupied at acidic and alkaline pH cause only a very modest unfolding of the protein's helical structure. Our data indicate the protonation-induced unfolding at room temperatures predominantly affects the Ω-loops of the protein. The two thermal transitions involve changes of two foldons, i.e. the unfolding of two short ß-strand segments (associated with the yellow foldon) followed by the unfolding of the 60' helix (green foldon) that connects the two Ω-loops of the protein. Apparently, intra-backbone hydrogen bonding is strong enough to mostly protect the terminal N- and C-helices from unfolding even at rather extreme conditions.

Dramatic tuning of ligand donor properties in (Ttz)CuCO through remote binding of H+ (Ttz = hydrotris(triazolyl)borate).

Complexes with bulky hydrotris(triazolyl)borate (Ttz) ligands, TtzCuCO, were used to probe how acids change the donor properties of Ttz ligands. (Ttz(tBu,Me))CuCO shows four distinct protonation states and a gradual increase in the CO stretch. The increased electrophilic nature of the Cu center upon protonation leads to enhanced C-H activation catalysis.

The (not completely irreversible) population of a misfolded state of cytochrome c under folding conditions.

This paper reports the discovery of a (meta)stable partially unfolded state of horse heart ferricytochrome c that was obtained after exposing the protein to a solution with an alkaline pH of 11.5 for 1 week. Thereafter, the protein did not undergo any detectable change in its secondary and tertiary structure upon adjusting the solution to folding promoting conditions at neutral pH. Spectroscopic data suggest that the misfolded protein exhibits a hexacoordinated low-spin state with a hydroxyl ion as the likely ligand. Below pH 6, a new ligation state emerges with the spectroscopic characteristics of a pentacoordinated quantum mixed state of the heme iron. Gel electrophoresis revealed substantial formation of soluble dimers and trimers at submillimolar concentrations, whereas monomers were dominant at lower, micromolar concentrations. Ultraviolet circular dichroism spectra indicate that oxidized monomers are pre-molten globule to globule-like with a substantial fraction of secondary (helical) structure reminiscent of alkaline state V. The oligomers contain even more helical structure, which suggests domain swapping as the underlying mechanism of their formation. A substantial fraction of the submillimolar mixture of monomers and oligomers underwent a reduction of the heme iron. Its dependence on pH suggests the coupling to a proton transfer process. Altogether, our data indicate a partially unfolded ferricytochrome c conformation with spectroscopic characteristics reminiscent of the recently discovered alkaline isomer V(b), which is stabilized under folding conditions by exposing the protein to a very alkaline pH for an extended period of time.

Structure analysis of unfolded peptides I: vibrational circular dichroism spectroscopy.

Vibrational circular dichroism (VCD) spectroscopy is an invaluable spectroscopic techniques utilized to exploit the optical strength of vibrational transitions for structure analysis. In this chapter, we describe the protocol for measuring and self-consistently analyzing VCD and the corresponding FT-IR spectra of short peptides. This process involves the decomposition of the IR spectrum as well as simulations of the amide I band profiles in both spectra based on structural models of the peptides investigated. This type of spectral analysis should be complemented with similar investigations of Raman spectra, which are described in the subsequent chapter. The structural analysis of short, unfolded peptides described in this chapter can easily be extended for the analysis of longer unfolded peptides or even proteins. This is particularly important in view of the demonstrated biological relevance of intrinsically disordered peptides and proteins (IDPs).

Structural analysis of unfolded peptides by Raman spectroscopy.

Raman spectroscopy has positioned itself as an invaluable tool in the study of complex biological systems, consistently being used to obtain information illustrating a vast array of fundamental properties. Of primary interest, with respect to the focus of this chapter, are conformational changes of peptide backbones. For short peptides to larger biological systems this understanding can be extended to local hydrogen bonding interactions and the probing of other structural or organizational properties. With regard to unfolded peptides Raman spectroscopy can be used as a technique complementary to infrared (IR) and vibrational circular dichroism (VCD) spectroscopy. This chapter describes how high quality polarized Raman spectra of peptide can be recorded with a Raman microspectrometer and how the structure sensitive amide I band profiles of isotropic and anisotropic Raman scattering can be analyzed in conjunction with the respective IR and VCD profiles to obtain conformational distributions of short unfolded peptides.

The pH dependence of the 695 nm charge transfer band reveals the population of an intermediate state of the alkaline transition of ferricytochrome c at low ion concentrations.

We have measured and analyzed the pH dependence of the 695 nm charge transfer band of horse heart ferricytochrome c as a function of pH between 7.0 and 10.5 at high (50 mM) and low (0.5 mM) phosphate ion concentrations. Our data clearly reveal that the transition from the native state (III) to the two alkaline states (IV) involves two deprotonation steps which cannot be assigned to the two different lysine ligands associated with the two alkaline states. While the respective pK values are rather similar at high phosphate concentrations (9.23 and 9.14), they are clearly different at low anion concentrations (9.65 and 8.5). Apparently, the deprotonation that can be assigned to a pK of 8.5 populates an intermediate state termed III*, in which M80 is still an axial ligand. A comparison of Soret band CD spectra suggests that III* bears some similarity with the recently characterized thermally excited state IIIh. Our data suggest that the current picture of the alkaline transition is incomplete. The obtained results might be of relevance for characterizing the structure of ferricytochrome c bound to anionic phospholipids.

Conformational stability of cytochrome C probed by optical spectroscopy.

Over the last 50 years cytochrome c has been used as a model system for studying electron transfer and protein folding processes. Recently, convincing evidence has been provided that this protein is also involved in other biological processes such as the apoptosis and α-synuclein aggregation. Numerous lines of evidence suggest that the diversity of the functional properties of cytochrome c is linked to its conformational plasticity. This chapter introduces circular dichroism and absorption spectroscopy, as an ideal tool to explore this protein's conformational in solution. Besides assisting in distinguishing different conformations and in obtaining the equilibrium thermodynamics of the transitions between them, the two spectroscopies can also be used to explore details of heme-protein interaction, for example, the influence of the external electric field on the prosthetic heme group.

Cu(II) and Ni(II) interactions with the terminally blocked hexapeptide Ac-Leu-Ala-His-Tyr-Asn-Lys-amide model of histone H2B (80-85).

The N- and C-terminal blocked hexapeptide Ac-Leu-Ala-His-Tyr-Asn-Lys-amide (LAHYNK) representing the 80-85 fragment of histone H2B was synthesized and its interactions with Cu(II) and Ni(II) ions were studied by potentiometric, UV-Vis, CD, EPR, and NMR spectroscopic techniques in solution. Our data reveal that the imidazole N(3) nitrogen atom is the primary ligating group for both metal ions. Sequential amide groups deprotonation and subsequent coordination to metal ions indicated an {N(imidazole), 3N(amide)} coordination mode above pH approximately 9, in all cases. In the case of Cu(II)-peptide system, the almost exclusive formation of the predominant species CuL in neutral media accounting for almost 98% of the total metal ion concentration at pH 7.3 strongly indicates that at physiological pH values the sequence -LAHYNK- of histone H2B provides very efficient binding sites for metal ions. The imidazole pyrrole N(1) ionization (but not coordination) was also detected in species CuH(-4)L present in solution above pH approximately 11.