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GSAFold - Protein Structure Prediction

Proteins are the building blocks of cells and the executioners of nearly all cellular functions. Their structure is of paramount importance to understand their dynamics and function, as well as the interactions with other molecules.

In this work, we apply the Generalized Simulated Annealing (GSA) to the prediction of protein structures in a new software. The GSA is a stochastic search algorithm employed in energy minimization and used in global optimization problems, such as gravity models, fitting of numerical data and conformation optimization of small molecules. Our software applies the analytical inverse of the probability distribution from GSA, a new method to apply rotations to the phi and psi angles of the peptide bonds and side chains, faster connection with NAMD for potential energy calculation and the possibility of parallel execution, granting a new take on ab-initio protein structure prediction. The new design also allows for an easier inclusion of knowledge derived potentials, based on experimentally determined protein structures.

We present results for the 14 amino acid protein mastoparan-X. The chain folds with RMSD of 3.0 angstroms after 500.000 GSA steps.> Currently, for this system, the software calculates 5 million GSA steps in less than 2 hours using just 4 processors.

Predicted structures can be refined with molecular dynamics simulations and used to study proteins whose conformation cannot be determined with experimental methods.

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Antiangiogenic Protein Endostatin: A MD study

Cover Page Article - Proteins - Volume 79, Issue 9

Endostatin is a potent antiangiogenic protein derived from the noncollagenous domain 1 (NC1) of collagen XVIII. The mechanism by which endostatin exerts its antiangiogenic effect is still incompletely understood. It has been shown that the 27 amino acid N-terminal fragment of murine endostatin has antitumor, antimigration, and antipermeability activities comparable to the full soluble protein. To understand how this peptide can exert such elaborate function, we performed structural analysis using molecular dynamics to evaluate the behavior of this fragment in aqueous environment. Here, we show that the N-terminal peptide of murine endostatin is able to assume a well-defined structure, folding into a zinc-dependent β-hairpin conformation. Analyzing the folding mechanism, we were able to understand why the N-terminal peptide of human endostatin with the same length failed to acquire a stable conformation. Conversely, we were able to predict the successful folding of the R4Q mutant and of a shorter form of the human peptide with 25 residues. Finally, we show that the β-hairpin conformation assumed by the zinc-bound peptide of murine endostatin has a high structural similarity with fragments of another family of angiogenesis inhibitors: the integrin-binding portion of the NC1 domain of collagen IV. Indeed, our docking simulations show that arresten, canstatin, and the endostatin peptide bind to the same spot of αVβ3 integrin, suggesting similar interactions via a common binding site on this receptor.

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Teaching Biochemistry Trough Videos

Is under development at our lab a new way to teach biochemistry using videos from molecular simulations. These videos can help high-school and undergrad students to better understand biochemical process, such as an enzymatic reaction.

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