The Protein Folding Problem: A Biophysical Enigma

Abstract

Protein folding, the problem of how an amino acid sequence folds into a unique three-dimensional shape, has been a long-standing problem in biology. The success of genome-wide sequencing efforts has increased the interest in understanding the protein folding enigma, because realizing the value of the genomic sequences rests on the accuracy with which the encoded gene products are understood. Although a complete understanding of the kinetics and thermodynamics of protein folding has remained elusive, there has been considerable progress in techniques to predict protein structure from amino acid sequences. The prediction techniques fall into three general classes: comparative modeling, threading and ab initio folding. The current state of research in each of these three areas is reviewed here in detail. Efforts to apply each method to proteome-wide analysis are reviewed, and some of the key technical hurdles that remain are presented. Protein folding technologies, while not yet providing a full understanding of the protein folding process, have clearly progressed to the point of being useful in enabling structure-based annotation of genomic sequences.

Biophysical Comparability of the Same Protein From Different Manufacturers: A Case Study Using Epoetin Alfa From Epogen® and Eprex®

“…Numerous research labs have demonstrated that proteins with equivalent amino acid sequences should fold into the same tertiary structure 22–26. While the Epoetin alfa from Epogen and Eprex have the same amino acid sequence, we detected differences in their biophysical characteristics.…”

Protein dynamics and motions in relation to their functions: several case studies and the underlying mechanisms

“…Even more importantly, such combined MD approaches enhance substantially the efficiency of sampling for protein conformational space, leading to their applications in ab initio folding, investigating the protein folding mechanism, and constructing the FEL of the protein-solvent system. For details, refer to (Fetrow et al, 2002; Henzler-Wildman & Kern, 2007; Liu et al, 2012). …”

“…Consequently, computational solution to the prediction of protein structure becomes the subject of intense activity. The computational structural prediction methodologies are often divided into three main categories: comparative modeling, fold recognition or threading, and ab initio folding methods (Fetrow, Giammona, Kolinski, & Skolnick, 2002). These methods involve the development of an energy function capable of identifying the most stable conformation of a protein and a scoring function for evaluating the predicted models.…”

Computational Methods for Protein Fold Prediction: an Ab-initio Topological Approach

“…Computational approaches to predict protein three-dimensional conformations are usually classified as homology modeling (or comparative modeling), fold recognition (or threading) and folding ab initio (see, for example, [18]). …”