Deconstructing Chaos: The Role of Pitch Hierarchy in Music Perception

During the early twentieth century, art music composers pushed Western tonality to the limits and eventually abandoned tonality altogether, creating a system that treated every pitch equally. This atonal system broke down all keys and harmonic progressions that are cornerstones of Western musical pitch hierarchy. Through an extensive review of current literature, this research aims to show that the concept of hierarchy, present in tonal but not atonal music, is central to music perception. This presentation will explore the role hierarchy in music perception through several means: examining the physical nature of sound on a mathematical basis, determining innate structures of music perception and investigating the neurobiology of tonal perception. Research will also seek to understand structural aspects of atonal music and how these structures are perceived, with the final conclusion that atonal musical structures do not facilitate music perception to the same degree as tonal structures since they lack fundamental pitch hierarchy

Dancing Through Life: Allosteric Transitions and Structural Analysis of Hsp70 and Hsp110 Chaperone Proteins

The molecular chaperone protein Hsp70 is centrally involved in cellular homeostasis by assisting in the folding and degradation of protein substrates. Hsp70 is joined by co-chaperones, such as Hsp110, which contribute to specialized tasks of the Hsp70 complex. Imbalances of this heat shock protein system are believed to be involved with the deregulation of cancer pathways and other human diseases. Better understanding of how these heat shock proteins work at the molecular level, which has been investigated using molecular docking tools, will give more clues about biological function. Simulating the formation and function of Hsp70 based chaperone complexes could provide new information about the control and regulation of these processes and well as new areas of exploration for drug discovery

Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones

Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes

Dancing through Life: Molecular Dynamics Simulations and Network-Centric Modeling of Allosteric Mechanisms in Hsp70 and Hsp110 Chaperone Proteins

Hsp70 and Hsp110 chaperones play an important role in regulating cellular processes that involve protein folding and stabilization, which are essential for the integrity of signaling networks. Although many aspects of allosteric regulatory mechanisms in Hsp70 and Hsp110 chaperones have been extensively studied and significantly advanced in recent experimental studies, the atomistic picture of signal propagation and energetics of dynamics-based communication still remain unresolved. In this work, we have combined molecular dynamics simulations and protein stability analysis of the chaperone structures with the network modeling of residue interaction networks to characterize molecular determinants of allosteric mechanisms. We have shown that allosteric mechanisms of Hsp70 and Hsp110 chaperones may be primarily determined by nucleotide-induced redistribution of local conformational ensembles in the inter-domain regions and the substrate binding domain. Conformational dynamics and energetics of the peptide substrate binding with the Hsp70 structures has been analyzed using free energy calculations, revealing allosteric hotspots that control negative cooperativity between regulatory sites. The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate binding regions. A smaller allosteric network in Hsp110 structures may elicit an entropy-driven allostery that occurs in the absence of global structural changes.We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications. The network- centric analysis of allosteric interactions has also established that centrality of functional residues could correlate with their sensitivity to mutations across diverse chaperone functions. This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones

Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

<div><p>Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions. A novel aspect of this work is the incorporation of dynamic residue correlations and coevolutionary residue dependencies in the construction of allosteric interaction networks and signaling pathways. We found that functional sites involved in allosteric regulation of Hsp70 may be characterized by structural stability, proximity to global hinge centers and local structural environment that is enriched by highly coevolving flexible residues. These specific characteristics may be necessary for regulation of allosteric structural transitions and could distinguish regulatory sites from nonfunctional conserved residues. The observed confluence of dynamics correlations and coevolutionary residue couplings with global networking features may determine modular organization of allosteric interactions and dictate localization of key mediating sites. Community analysis of the residue interaction networks revealed that concerted rearrangements of local interacting modules at the inter-domain interface may be responsible for global structural changes and a population shift in the DnaK chaperone. The inter-domain communities in the Hsp70 structures harbor the majority of regulatory residues involved in allosteric signaling, suggesting that these sites could be integral to the network organization and coordination of structural changes. Using a network-based formalism of allostery, we introduced a community-hopping model of allosteric communication. Atomistic reconstruction of signaling pathways in the DnaK structures captured a direction-specific mechanism and molecular details of signal transmission that are fully consistent with the mutagenesis experiments. The results of our study reconciled structural and functional experiments from a network-centric perspective by showing that global properties of the residue interaction networks and coevolutionary signatures may be linked with specificity and diversity of allosteric regulation mechanisms.</p></div

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone.

The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK family are of particular interest as functional diversification among these kinases may be related to variations in chaperone dependencies and can be exploited in drug discovery of personalized therapeutic agents. In this work, we report the results of a computational investigation of several members of CDK family (CDK5, CDK6, CDK9) that represented a broad repertoire of chaperone dependencies-from nonclient CDK5, to weak client CDK6, and strong client CDK9. By using molecular simulations of multiple crystal structures we characterized conformational ensembles and collective dynamics of CDK proteins. We found that the elevated dynamics of CDK9 can trigger imbalances in cooperative collective motions and reduce stability of the active fold, thus creating a cascade of favorable conditions for chaperone intervention. The ensemble-based modeling of residue interaction networks and community analysis determined how differences in modularity of allosteric networks and topography of communication pathways can be linked with the client status of CDK proteins. This analysis unveiled depleted modularity of the allosteric network in CDK9 that alters distribution of communication pathways and leads to impaired signaling in the client kinase. According to our results, these network features may uniquely define chaperone dependencies of CDK clients. The perturbation response scanning and rigidity decomposition approaches identified regulatory hotspots that mediate differences in stability and cooperativity of allosteric interaction networks in the CDK structures. By combining these synergistic approaches, our study revealed dynamic and network signatures that can differentiate kinase clients and rationalize subtle divergences in the activation mechanisms of CDK family members. The therapeutic implications of these results are illustrated by identifying structural hotspots of pathogenic mutations that preferentially target regions of the increased flexibility to enable modulation of activation changes. Our study offers a network-based perspective on dynamic kinase mechanisms and drug design by unravelling relationships between protein kinase dynamics, allosteric communications and chaperone dependencies

Analysis of High Centrality Residues in Sse1p Structures.

<p>Structural mapping of common peaks in the force constant and network centrality distributions onto Sse1p conformations (A, B). The structures are shown in a ribbon representation and main structural elements, including subdomains and functional residues are annotated and colored according to the adopted scheme. The functional residues of high centrality are shown in spheres and colored according to their respective subdomains. Structural positions of high centrality functional residues are indicated by arrows. The probability distributions of residue centrality in the Sse1p-ATP (C) and Sse1p in a complex with the NBD of hHsp70 (D). These profiles were obtained from MD trajectories by averaging computations of residue centrality over all protein residues in the conformational ensembles.</p

The Relationships between Coevolutionary and Residue Interaction Network Parameters in the Hsp70 Proteins.

<p>(A) A scatter graph of cMI residue scores and residue centrality values. (B) A scatter plot of pMI residue scores and residue centrality values. The data points (shown in black filled squares) aggregated coevolutionary propensities and residue centrality profiles in all simulated Hsp70 proteins. pMI scores and residue centrality values were evaluated by averaging computations over MD-based conformational ensembles of the following Hsp70 structures: DnaK_GEOKA (pdb is 2V7Y) DNAK_ECOLI (pdb id 2KHO, 4B9Q, 4JNE, 4JN4), HS7C_BOVIN (pdb id 1YUW, 4FL9), and HSP7F_YEAST (Hsp homolog Sse1) proteins (pdb id 2QXL, 3C7N, 3D2E, 3D2F). Functional sites of allosteric regulation in the DnaK chaperone are highlighted as gold filled squares. These residues include K70, R71 (subdomain IB), P143, Y145, F146, D148, R151, K155, R167, I168, N170, E171 (subdomain IA), D393 (inter-domain linker), K414, N415, I438, V440, Q442, L454, D431, R467, D481, L484 (SBD-β subdomain), M515, D540, H544 (SBD-α subdomain). The frequency distributions of pMI scores (C) and residue centrality (D) in the Hsp70 structures are shown for all residues (in blue bars) and for functional residues (in green bars). All experimentally known functional sites of the Hsp70 proteins were included in these frequency distributions.</p