Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases

A framework for analysing learning health systems: Are we removing the most impactful barriers?

Objective: Learning Health Systems (LHS) are one of the major computing advances in healthcare. However, no prior research has systematically analysed barriers and facilitators for LHS. This paper presents an investigation into the barriers, benefits and facilitating factors for LHS in order to create a basis for their successful implementation and adoption. Method: First, the ITPOSMO-BBF framework was developed based on the established ITPOSMO (Information, Technology, Processes, Objectives, Staffing, Management and Other factors) framework, extending it for analysing barriers, benefits and facilitators. Second, the new framework was applied to LHS. Results: We found that LHS shares similar barriers and facilitators with Electronic Health Records (EHR); in particular, most facilitator effort in implementing EHR and LHS goes towards barriers categorised as human factors, even though they were seen to carry fewer benefits. Barriers whose resolution would bring significant benefits in safety, quality and health outcomes remain. Discussion: LHS envisage constant generation of new clinical knowledge and practice based on the central role of collections of EHR. Once LHS are constructed and operational, they trigger new data streams into the EHR. So LHS and EHR have a symbiotic relationship. The implementation and adoption of EHRs has proved and continues to prove challenging and there are many lessons for LHS arising from these challenges. Conclusion: Successful adoption of LHS should take account of the framework proposed in this paper, especially with respect to its focus on removing barriers that have the most impact

Mechanisms of Intramolecular Communication in a Hyperthermophilic Acylaminoacyl Peptidase: A Molecular Dynamics Investigation

Protein dynamics and the underlying networks of intramolecular interactions and communicating residues within the three-dimensional (3D) structure are known to influence protein function and stability, as well as to modulate conformational changes and allostery. Acylaminoacyl peptidase (AAP) subfamily of enzymes belongs to a unique class of serine proteases, the prolyl oligopeptidase (POP) family, which has not been thoroughly investigated yet. POPs have a characteristic multidomain three-dimensional architecture with the active site at the interface of the C-terminal catalytic domain and a β-propeller domain, whose N-terminal region acts as a bridge to the hydrolase domain. In the present contribution, protein dynamics signatures of a hyperthermophilic acylaminoacyl peptidase (AAP) of the prolyl oligopeptidase (POP) family, as well as of a deletion variant and alanine mutants (I12A, V13A, V16A, L19A, I20A) are reported. In particular, we aimed at identifying crucial residues for long range communications to the catalytic site or promoting the conformational changes to switch from closed to open ApAAP conformations. Our investigation shows that the N-terminal α1-helix mediates structural intramolecular communication to the catalytic site, concurring to the maintenance of a proper functional architecture of the catalytic triad. Main determinants of the effects induced by α1-helix are a subset of hydrophobic residues (V16, L19 and I20). Moreover, a subset of residues characterized by relevant interaction networks or coupled motions have been identified, which are likely to modulate the conformational properties at the interdomain interface

Compact Encoding of Non-adjacent Forms with Applications to Elliptic Curve Cryptography

Techniques for fast exponentiation (multiplication) in various groups have been extensively studied for use in cryptographic primitives. Specifically

Mandate for remote sensing education and the remote sensing core curriculum

Consensus was developed by the remote sensing community during the 1980s and early 1990s regarding the need for an organized approach to teaching remote sensing fundamentals for collegiate institutions. Growth of the remote sensing industry might be seriously hampered without concerted efforts to bolster the capacity to teach state-of-the-practice remote sensing theory and practice to the next generation of professionals. A concerted effort of educators, researchers, government, and industry began in 1992 to meet these demands leading to the creation of the Remote Sensing Core Curriculum. The RSCC is currently sustained by cooperative efforts of the ASPRS, ICRSE, NASA, NCGIA, and others in the remote sensing community. Growth of the RSCC into the K-12 community resulted from its Internet teaching foundation that enables comprehensive and response reference links to the whole of the education community

Hemispheric processing of differently valenced and self-relevant attachment words in middle-aged married and separated individuals

The reliance in experimental psychology on testing undergraduate populations with relatively little life experience, and/or ambiguously valenced stimuli with varying degrees of self-relevance, may have contributed to inconsistent findings in the literature on the valence hypothesis. To control for these potential limitations, the current study assessed lateralised lexical decisions for positive and negative attachment words in 40 middle-aged male and female participants. Self-relevance was manipulated in two ways: by testing currently married compared with previously married individuals and by assessing self-relevance ratings individually for each word. Results replicated a left hemisphere advantage for lexical decisions and a processing advantage of emotional over neutral words but did not support the valence hypothesis. Positive attachment words yielded a processing advantage over neutral words in the right hemisphere, while emotional words (irrespective of valence) yielded a processing advantage over neutral words in the left hemisphere. Both self-relevance manipulations were unrelated to lateralised performance. The role of participant sex and age in emotion processing are discussed as potential modulators of the present findings