The Protein-Folding Problem, 50 Years On

Abstract

The protein-folding problem was first posed about one half-century ago. The term refers to three broad questions: (i) What is the physical code by which an amino acid sequence dictates a protein's native structure? (ii) How can proteins fold so fast? (iii) Can we devise a computer algorithm to predict protein structures from their sequences? We review progress on these problems. In a few cases, computer simulations of the physical forces in chemically detailed models have now achieved the accurate folding of small proteins. We have learned that proteins fold rapidly because random thermal motions cause conformational changes leading energetically downhill toward the native structure, a principle that is captured in funnel-shaped energy landscapes. And thanks in part to the large Protein Data Bank of known structures, predicting protein structures is now far more successful than was thought possible in the early days. What began as three questions of basic science one half-century ago has now grown into the full-fledged research field of protein physical science.

Folding and insertion thermodynamics of the transmembrane WALP peptide

“…This is true not only because protein structure prediction remains a formidable computational challenge, both for equilibration and force-field reasons. [8][9][10][11] We also face the additional predicament that a lipid bilayer and its surroundings constitute a very highly anisotropic environment, where everything from dielectric constants to lateral stresses varies dramatically on an Ångstrom scale, pushing both continuum theory and local thermodynamics to their limits. It should hence not come as a surprise that even ostensibly basic questions about structure, location, and interaction of small peptides in bilayers remain difficult to answer.…”

Gauge fields, strings, solitons, anomalies, and the speed of life

“…There is a relation between (38), the integrable hierarchy of the nonlinear Schrödinger (NLS) equation, and the Heisenberg spin chain. For this we follow Hasimoto [17] and combine the curvature and torsion into the complex variable (39) This yields us the standard NLS Hamiltonian density [18,19] …”

“…Like other high precision machines, the way proteins function can be very sensitive to their conformation. The protein folding problem was originally posed some 50 years ago, and it has since then assumed various incarnations [37][38][39]. The problem endures as one of the most important unresolved problems in science, it aims to explain what is life.…”

Reduced Fragment Diversity for Alpha and Alpha-Beta Protein Structure Prediction using Rosetta

“…Whereas performing protein folding simulation conforming to Newton's second law may appear as an attractive approach, it is only practical when applied on very small targets while using state-of-the-art supercomputers and grid computing [2] [3]. Consequently, many current computational methods rely on Monte Carlo simulations and heuristic search techniques besides reduction of amino acids and energy functions' representations [4] [5].…”