Abstract
Protein structure prediction (PSP) has been one of the most challenging problems in computational biology for several decades. The challenge is largely due to the complexity of the all-atomic details and the unknown nature of the energy function. Researchers have therefore used simplified energy models that consider interaction potentials only between the amino acid monomers in contact on discrete lattices. The restricted nature of the lattices and the energy models poses a twofold concern regarding the assessment of the models. Can a native or a very close structure be obtained when structures are mapped to lattices? Can the contact based energy models on discrete lattices guide the search towards the native structures? In this paper, we use the protein chain lattice fitting (PCLF) problem to address the first concern; we developed a constraint-based local search algorithm for the PCLF problem for cubic and face-centered cubic lattices and found very close lattice fits for the native structures. For the second concern, we use a number of techniques to sample the conformation space and find correlations between energy functions and root mean square deviation (RMSD) distance of the lattice-based structures with the native structures. Our analysis reveals weakness of several contact based energy models used that are popular in PSP.
Highlights
Proteins are one of the most important organisms in a living cell, virtually participating in almost every process within the cell including carrying oxygen, signaling cells, fighting infection, and performing metabolism
We developed a constraint-based local search algorithm for the protein chain lattice fitting (PCLF) problem for cubic and face-centered cubic lattices and found very close lattice fits for the native structures
We propose a constraint-based local search framework that produces state-of-the-art results for the protein chain lattice fitting (PCLF) problem for real proteins
Summary
Proteins are one of the most important organisms in a living cell, virtually participating in almost every process within the cell including carrying oxygen (by hemoglobin), signaling cells (by insulin), fighting infection (by antibodies), and performing metabolism (by enzymes). A protein has to fold into a native three-dimensional structure, which is unique, stable, and kinetically accessible [1] in a given environment. The nature of the energy function is yet unknown. Knowledge about the native structure is of paramount importance, specially for rational drug discovery and to understand the basics of life. Protein structure prediction (PSP) is one of the most challenging problems in biology. Given a primary amino acid sequence of protein, the task in PSP is to find its three-dimensional native structure that has the minimum free energy
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