Protein Folding

Description:
The protein folding problem was first recognized by Hsien Wu (1931) and Mirsky & Pauling (1936), approximately three-quarters of a century ago. The problem ‑ arguably the most significant unsolved problem in chemical biology ‑ is inherently grounded in protein thermodynamics, and thermodynamics is surely our most powerful discipline for understanding biological systems. So why does fundamental understanding of protein folding remain an unresolved question?

In work at the NIH, Anfinsen showed that a protein's three-dimensional structure is a spontaneous consequence of its amino acid sequence in water at physiological temperature and pressure. Remarkably, under dilute solution conditions, a purified protein adopts its native fold without either the addition of energy or assistance from auxiliary cellular components (chaperones notwithstanding). The fold of the protein links the one‑dimensional, linear world of DNA to the three-dimensional world of biological function; accordingly, protein folding is a cornerstone of life on earth. Yet, in essence, this self-assembly process lies within the province of biophysics, not cell biology.


The classic folding paradigm, established by Anfinsen and others, has been interpreted to mean that under folding conditions, the native fold is selected from an astronomical number of conceivable alternatives by the constellation of favorable interactions between and among its amino acid sidechains. This plausible idea is entirely consistent with the characteristic close-packing seen in protein crystal structures, where it is apparent that residues distant in sequence are juxtaposed in space, presumably providing both structural stability and topological specificity. Contrary to this view, I will discuss evidence from both experiment and simulations that the overall fold is established prior to eventual sidechain close-packing. Consequently, formation of the folded, hydrogen-bonded framework and its further stabilization via sidechain locking are separable folding events, an enormously simplifying realization.


The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
Author: Dr. George Rose
Runtime: 01:19:36
Permanent link: http://videocast.nih.gov/launch.asp?16130

Comentario

La predicción de la estructura secundaria de la proteína es el puente entre la secuencia y la determinación de su estructura tridimensional, la cual está implícita en la secuencia de aminoácidos enlazados por propiedades fisico-qímicas, también conocida como estructura primaria. Computacionalmente, una proteína se representa como una secuencia de símbolos de un alfabeto λ de 20 aminoácidos. Los aminoácidos de una secuencia se conocen como residuos.

λ = {A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y }

La forma de plegamiento resultante de la proteíına, en gran parte, es consecuencia de la secuencia de aminoácidos. El hecho de que las proteínas se plieguen solas de una manera tan fidedigna y eficiente es una paradoja aún no resuelta, formulada por primera vez por Levinthal: la búsqueda sistemática de la conformación nativa puede tomar millones de años, pero el tiempo real de plegamiento de una proteína oscila entre el microsegundo y el minuto. Existen algunas explicaciones de cómo sucede, pero aún no se tiene la verdad absoluta. Por lo pronto, el modelo computacional del plegamiento asume que la secuencia de residuos se pliega inicialmente conformando núcleos, para después compactarse hasta alcanzar estructura intermedia (estructura secundaria) que evolucionará hacia la terciaria. La estructura secundaria consiste involucra la organización espacial de la secuencia de aminoácidos en tres tipos de estructuras: hélices, hojas y giros. La predicción de estas estructuras es una tarea computacionalmente muy costosa.