Erratum: Signal propagation in proteins and relation to equilibrium fluctuations (PLoS Computational Biology (2007) 3, 9, (e172) DOI: 10.1371/journal.pcbi.0030172))

Elastic network (EN) models have been widely used in recent years for describing protein dynamics, based on the premise that the motions naturally accessible to native structures are relevant to biological function. We posit that equilibrium motions also determine communication mechanisms inherent to the network architecture. To this end, we explore the stochastics of a discrete-time, discrete-state Markov process of information transfer across the network of residues. We measure the communication abilities of residue pairs in terms of hit and commute times, i.e., the number of steps it takes on an average to send and receive signals. Functionally active residues are found to possess enhanced communication propensities, evidenced by their short hit times. Furthermore, secondary structural elements emerge as efficient mediators of communication. The present findings provide us with insights on the topological basis of communication in proteins and design principles for efficient signal transduction. While hit/commute times are information-theoretic concepts, a central contribution of this work is to rigorously show that they have physical origins directly relevant to the equilibrium fluctuations of residues predicted by EN models

Universal behavior of localization of residue fluctuations in globular proteins

Localization properties of residue fluctuations in globular proteins are studied theoretically by using the Gaussian network model. Participation ratio for each residue fluctuation mode is calculated. It is found that the relationship between participation ratio and frequency is similar for all globular proteins, indicating a universal behavior in spite of their different size, shape, and architecture.Comment: 4 pages, 3 figures. To appear in Phys. Rev.

Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle

Neurotransmitter: sodium symporters (NSSs) regulate neuronal signal transmission by clearing excess neurotransmitters from the synapse, assisted by the co-transport of sodium ions. Extensive structural data have been collected in recent years for several members of the NSS family, which opened the way to structure-based studies for a mechanistic understanding of substrate transport. Leucine transporter (LeuT), a bacterial orthologue, has been broadly adopted as a prototype in these studies. This goal has been elusive, however, due to the complex interplay of global and local events as well as missing structural data on LeuT N-terminal segment. We provide here for the first time a comprehensive description of the molecular events leading to substrate/Na+ release to the postsynaptic cell, including the structure and dynamics of the N-terminal segment using a combination of molecular simulations. Substrate and Na+-release follows an influx of water molecules into the substrate/Na+-binding pocket accompanied by concerted rearrangements of transmembrane helices. A redistribution of salt bridges and cation-π interactions at the N-terminal segment prompts substrate release. Significantly, substrate release is followed by the closure of the intracellular gate and a global reconfiguration back to outward-facing state to resume the transport cycle. Two minimally hydrated intermediates, not structurally resolved to date, are identified: one, substrate-bound, stabilized during the passage from outward- to inward-facing state (holo-occluded), and another, substrate-free, along the reverse transition (apo-occluded)

Stabilization of intermediate density states in globular proteins by homogeneous intramolecular attractive interactions

On-lattice simulations of two-dimensional self-avoiding chains subject to homogeneous intramolecular attractive interactions were performed as a model for studying various density regimes in globular proteins. For short chains of less than 15 units, all conformations were generated and classified by density. The range of intramolecular interactions was found to increase uniformly with density, and the average number of topological contacts is directly proportional to density. The uniform interaction energy increases the probability of high density states but does not necessarily lead to dominance of the highest density state. Typically, several large peaks appear in the probability distribution of packing densities, their location and amplitude being determined by the balance between entropic effects enhancing more expanded conformations and attractive interactions favoring compact forms. Also, the homogeneous interaction energy affects the distribution of most probable interacting points in favor of the longer range interactions over the short range ones, but in addition it introduces some more detailed preferences even among short range interactions. There are some implications about the characteristics of the intermediate density states and also for the likelihood that the native state does not correspond completely to the lowest energy conformation

Nonlinear kinetics of spinodal decomposition, and dissolution of inhomogeneities formed by spinodal decomposition in polymer blends

Nonlinear kinetics of both spinodal decomposition at early stages, and the dissolution of homogeneities formed during spinodal decomposition, is studied. Variation of the scattering intensity during a complete cycle consisting of a step temperature change from T1 in the one‐phase region to T2 in the two‐phase region, a period of spinodal decomposition followed by a temperature drop from T2 back to T1, and the subsequent relaxation to the original equilibrium state, is investigated at various wavenumbers. Step temperature changes within one‐phase region are also investigated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113684/1/19920620107_ftp.pd

The Use of Experimental Structures to Model Protein Dynamics

The number of solved protein structures submitted in the Protein Data Bank (PDB) has increased dramatically in recent years. For some specific proteins, this number is very high—for example, there are over 550 solved structures for HIV-1 protease, one protein that is essential for the life cycle of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS) in humans. The large number of structures for the same protein and its variants include a sample of different conformational states of the protein. A rich set of structures solved experimentally for the same protein has information buried within the dataset that can explain the functional dynamics and structural mechanism of the protein. To extract the dynamics information and functional mechanism from the experimental structures, this chapter focuses on two methods—Principal Component Analysis (PCA) and Elastic Network Models (ENM). PCA is a widely used statistical dimensionality reduction technique to classify and visualize high-dimensional data. On the other hand, ENMs are well-established simple biophysical method for modeling the functionally important global motions of proteins. This chapter covers the basics of these two. Moreover, an improved ENM version that utilizes the variations found within a given set of structures for a protein is described. As a practical example, we have extracted the functional dynamics and mechanism of HIV-1 protease dimeric structure by using a set of 329 PDB structures of this protein. We have described, step by step, how to select a set of protein structures, how to extract the needed information from the PDB files for PCA, how to extract the dynamics information using PCA, how to calculate ENM modes, how to measure the congruency between the dynamics computed from the principal components (PCs) and the ENM modes, and how to compute entropies using the PCs. We provide the computer programs or references to software tools to accomplish each step and show how to use these programs and tools. We also include computer programs to generate movies based on PCs and ENM modes and describe how to visualize them

Anharmonicity and self-similarity of the free energy landscape of protein G

The near-native free energy landscape of protein G is investigated through 0.4 microseconds-long atomistic molecular dynamics simulations in explicit solvent. A theoretical and computational framework is used to assess the time-dependence of salient thermodynamical features. While the quasi-harmonic character of the free energy is found to degrade in a few ns, the slow modes display a very mild dependence on the trajectory duration. This property originates from a striking self-similarity of the free energy landscape embodied by the consistency of the principal directions of the local minima, where the system dwells for several ns, and of the virtual jumps connecting them.Comment: revtex, 6 pages, 5 figure

Perilaku Pencarian Pengobatan Selama Kehamilan pada Ibu Hamil dan Ibu Menyusui di Wilayah Kerja Puskesmas Konda Kecamatan Konda Kabupaten

Perawatan kehamilan merupakan pelayanan kesehatan oleh tenaga kesehatan untuk ibu selamamasa kehamilannya, dilaksanakan sesuai dengan standar pelayanan antenatal yang ditetapkan.Penelitian ini bertujuan untuk mengetahui gambaran pencarian pengobatan oleh masyarakatkhususnya pada ibu hamil dan ibu menyusui selama kehamilan di wilayah Kerja PuskesmasPuskesmas Konda, Kecamatan Konda, Kabupaten Konawe Selatan Tahun 2016 ditinjau dari aspekpencarian pengobatan, pengetahuan, dukungan keluarga, akses, dan keyakinan. Jenis penelitianyang digunakan adalah penelitian deskriptif, selanjutnya pengumpulan dan pengolahan datadilakukan dengan pendekatan kuantitatif. Populasi pada penelitian ini adalah seluruh ibu hamildan ibu menyusui pada Wilayah Puskesmas Konda Kabupaten Konawe Selatan Tahun 2016sebanyak 293 orang. Sampel dalam penelitian ini yaitu sebanyak 74, Sampel responden diambildengan teknik simple random sampling. Hasil penelitian menunjukkan bahwa responden yangmencari pengobatan ke sektor profesional 63 responden (85,1%) sedangkan yang mencaripengobatan ke sektor tradisional 11 responden (14,9%) dan mengobati sendiri sebanyak 0responden (0%), berdasarkan pengetahuan menunjukkan bahwa terdapat 64 responden (86,5%)berada pada kategori cukup dan 10 responden (13,5%) berada pada kategori kurang, berdasarkandukungan keluarga menunjukkan bahwa terdapat 63 responden (85,1%) yang mendapatdukungan keluarga dan 11 responden (14,9%) tidak memiliki dukungan keluarga, berdasarkanakses menunjukan bahwa terdapat 63 responden (85,1%) mudah mengakses pelayanankesehatan di puskesmas dan 11 responden (14,9%) sulit mengakses pelayanan kesehatan dipuskesmas dari tempat tinggalnya dan berdasarkan keyakinan menunjukkan bahwa terdapat 55responden (74,3%) yang menyatakan ada keyakinannya dan 19 responden 25,7 yang tidak adakeyakinannya

TURKEY AND THE RESCUE OF JEWS DURING THE NAZI ERA: A REAPPRAISAL OF TWO CASES; GERMAN-JEWISH SCIENTISTS IN TURKEY & TURKISH JEWS IN OCCUPIED FRANCE

The study aims to investigate in depth two incidents that have been widely presented in literature as examples of the humanitarian and compassionate Turkish Republic lending her helping hand to Jewish people who had fallen into difficult, even life threatening, conditions under the racist policies of the Nazi German regime. The first incident involved recruiting more than one hundred Jewish scientists and skilled technical personnel from German-controlled Europe for the purpose of reforming outdated academia in Turkey. The second incident is the rescue of Jews of Turkish origin as well as those of non-Turkish origin from France during WWII. Both events were vociferously introduced for the first time in the early 1990s, within the discourse of the Quincentennial Foundation founded to commemorate the five hundreth year of immigration of Jews to the Ottoman Empire following their expulsion from Spain in 1492. Our study shows that behind the Turkish recruitment of German-Jewish scholars, it was not humanitarian motives, but the interest of the Turkish state was the main and only motivation and the Jewishness of those scientists did not play any role in the decision of their employment. The study also shows that the Turkish government did not appear to have shown any concrete intention to rescue its Jewish citizens in France who were under the threat of deportations, particularly in the last months of 1942. On the contrary, with mass denaturalization policies, the government was reluctant to take back a sizable portion of its Jewish citizens in France. Only in December 1943, with the obvious defeat of Germany on the horizon and with the realization that only a small number of Jewish citizens would return, did the government give consent to their transportation to Turkey. The sources analyzed also do not confirm an unconventional or special altruistic act of the Turkish diplomats in France in relation to protecting or saving Jewish victims at that time

Markov propagation of allosteric effects in biomolecular systems: application to GroEL–GroES

We introduce a novel approach for elucidating the potential pathways of allosteric communication in biomolecular systems. The methodology, based on Markov propagation of ‘information' across the structure, permits us to partition the network of interactions into soft clusters distinguished by their coherent stochastics. Probabilistic participation of residues in these clusters defines the communication patterns inherent to the network architecture. Application to bacterial chaperonin complex GroEL–GroES, an allostery-driven structure, identifies residues engaged in intra- and inter-subunit communication, including those acting as hubs and messengers. A number of residues are distinguished by their high potentials to transmit allosteric signals, including Pro33 and Thr90 at the nucleotide-binding site and Glu461 and Arg197 mediating inter- and intra-ring communication, respectively. We propose two most likely pathways of signal transmission, between nucleotide- and GroES-binding sites across the cis and trans rings, which involve several conserved residues. A striking observation is the opposite direction of information flow within cis and trans rings, consistent with negative inter-ring cooperativity. Comparison with collective modes deduced from normal mode analysis reveals the propensity of global hinge regions to act as messengers in the transmission of allosteric signals