Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8.
Elmar Krieger,Keehyoung Joo,Jinwoo Lee,Jooyoung Lee,Srivatsan Raman,James Thompson,Michael D. Tyka,David Baker,Kevin Karplus +8 more
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TLDR
In this article, the authors describe four approaches that address the last mile of the protein folding problem and have performed well during CASP8, yielding physically realistic models: YASARA, which runs molecular dynamics simulations of models in explicit solvent, using a new partly knowledge-based all atom force field derived from Amber.Abstract:
A correct alignment is an essential requirement in homology modeling. Yet in order to bridge the structural gap between template and target, which may not only involve loop rearrangements, but also shifts of secondary structure elements and repacking of core residues, high-resolution refinement methods with full atomic details are needed. Here, we describe four approaches that address this "last mile of the protein folding problem" and have performed well during CASP8, yielding physically realistic models: YASARA, which runs molecular dynamics simulations of models in explicit solvent, using a new partly knowledge-based all atom force field derived from Amber, whose parameters have been optimized to minimize the damage done to protein crystal structures. The LEE-SERVER, which makes extensive use of conformational space annealing to create alignments, to help Modeller build physically realistic models while satisfying input restraints from templates and CHARMM stereochemistry, and to remodel the side-chains. ROSETTA, whose high resolution refinement protocol combines a physically realistic all atom force field with Monte Carlo minimization to allow the large conformational space to be sampled quickly. And finally UNDERTAKER, which creates a pool of candidate models from various templates and then optimizes them with an adaptive genetic algorithm, using a primarily empirical cost function that does not include bond angle, bond length, or other physics-like terms.read more
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Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces
TL;DR: HOPE is described, a fully automatic program that analyzes the structural and functional effects of point mutations and builds a report with text, figures, and animations that is easy to use and understandable for (bio)medical researchers.
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A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions
TL;DR: A new version of the backbone-dependent rotamer library has been developed using adaptive kernel density estimates for the rotamer frequencies and adaptive kernel regression for the mean dihedral angles and variances to allow for evaluation of therotamer probabilities, mean angles, andvariances as a smooth and continuous function of phi and psi.
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The PDB_REDO server for macromolecular structure model optimization.
TL;DR: Algorithms are presented that allowed a web-server implementation of PDB_REDO, and the first user results are discussed.
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New ways to boost molecular dynamics simulations
Elmar Krieger,Gert Vriend +1 more
TL;DR: A set of algorithms that allow to simulate dihydrofolate reductase (DHFR, a common benchmark) with the AMBER all‐atom force field at 160 nanoseconds/day on a single Intel Core i7 5960X CPU are described.
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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
TL;DR: Increasing evidence suggests that the effect of APOE*ε4 on AD risk is exerted through inhibition of amyloid-β (Aβ) clearance and promotion of Aβ aggregation, although the relevance of this observation to AD pathogenesis requires further investigation.
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