Jose Borreguero

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An improved TASSER (Threading/ASSEmbly/Refinement) methodology is applied to predict the tertiary structure for all CASP7 targets. TASSER employs template identification by threading, followed by tertiary structure assembly by rearranging continuous template fragments, where conformational space is searched via Parallel Hyperbolic Monte Carlo sampling with(More)
Understanding the toxicity of amyloidogenic protein aggregates and designing therapeutic approaches require the knowledge of their structure at atomic resolution. Although solid-state NMR, X-ray diffraction, and other experimental techniques are capable of discerning the protein fibrillar structure, determining the structures of early aggregates, called(More)
Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138, USA We perform a detailed analysis of the thermodynamics and folding kinetics of the SH3 domain fold with discrete molecular dynamic simulations. We propose a protein model that reproduces some of the experimentally observed thermodynamic and folding kinetic properties of(More)
The transition-state ensemble (TSE) is the set of protein conformations with an equal probability to fold or unfold. Its characterization is crucial for an understanding of the folding process. We determined the TSE of the src-SH3 domain protein by using extensive molecular dynamics simulations of the Go model and computing the folding probability of a(More)
The aggregation of -helix-rich proteins into -sheet-rich amyloid fibrils is associated with fatal diseases, such as Alzheimer’s disease and prion disease. During an aggregation process, protein secondary structure elements— -helices— undergo conformational changes to -sheets. The fact that proteins with different sequences and structures undergo a similar(More)
Experimental observations suggest that proteins follow different folding pathways under different environmental conditions. We perform molecular dynamics simulations of a model of the c-Crk SH3 domain over a broad range of temperatures, and identify distinct pathways in the folding transition. We determine the kinetic partition temperature-the temperature(More)
The aggregation of alpha-helix-rich proteins into beta-sheet-rich amyloid fibrils is associated with fatal diseases, such as Alzheimer's disease and prion disease. During an aggregation process, protein secondary structure elements-alpha-helices-undergo conformational changes to beta-sheets. The fact that proteins with different sequences and structures(More)
Oligomeric, neurotoxic amyloid protein assemblies are thought to be causative agents in Alzheimer's and other neurodegenerative diseases. Development of oligomer-specific therapeutic agents requires a mechanistic understanding of the oligomerization process. This is a daunting task because amyloidogenic protein oligomers often are metastable and comprise(More)
We study cold denaturation of proteins at high pressures. Using multicanonical Monte Carlo simulations of a model protein in a water bath, we investigate the effect of water density fluctuations on protein stability. We find that above the pressure where water freezes to the dense ice phase (≈ 2 kbar), the mechanism for cold denaturation with decreasing(More)
A critical open problem in \emph{ab initio} protein folding is protein energy function design, which pertains to defining the energy of protein conformations in a way that makes folding most efficient and reliable. In this paper, we address this issue as a weight optimization problem and utilize a machine learning approach, learning-to-rank, to solve this(More)