Introduction

Abstract

Every new scientific discovery unleashes a new excitement and fresh concerns: generates several valid and invalid questions. Some people will be in favor of that some oppose. Linus Pauling and Robert Corey published several papers on the inner workings of proteins—molecules regarded as the building blocks of life—which are the key to understanding biology at the molecular level. They might or might not have realized that they are throwing a very important and essential problem to solve for getting the answer of the existence of biological life in this universe. Protein folding problems (PFP) started with the discovery of the structure of the first protein and attracted attention from all kinds of people irrespective of their fields. But this also started a long ongoing quest to answer how these structures form. Over the last 50 years, enormous advancement has been made to understand protein folding mechanisms. But consensus between experimental and theoretical explanation has not reached. Both these approaches are in agreement to some extent for small and simple peptides, but for large and complex proteins any agreement is quite far. PFP has three important questions: (a) thermodynamic question: how inter-atomic forces act on an amino acid sequence, (b) Kinetic question: how protein can fold so fast, and (c) computational/technological question: how to predict protein structure. In fact, every protein is unique in its structure and function. Even the homologous proteins are different in their organizations. Part of the problem lies in our approach in designing experiments for studying this phenomenon. We mostly use recombinant protein and study folding-unfolding in the non-native environment using buffer, temperature, chaotropic agents, or protecting osmolytes. We ignore a very important aspect that these are not the natural environment of the protein, and that is the reason why we have a time-lag of denaturation/renaturation process in biochemical labs in comparison to biological lab, the cell. The natural environment of a protein is the cellular environment. When we want to study and get some definite answer then we need to look into this problem in a holistic manner. We need to design our experiment such that we can learn the choreography of this process in its natural milieu, which can be extrapolated to outside environment. Another option for solving PFP is using inverse protein folding (IPF) approach. Here the question is exactly opposite to what we were considering earlier. How the requisite sequence emerges from the functional need for the conformation via evolution or any other method of sequence selection. So, first choose required fold and get the stable fast folding amino acid sequences. In other word, natural end of IFP is the prediction of stable fast folding sequence which folds in situ to biologically useful target conformation/ensemble. A solution to protein folding problem is of enormous intellectual importance, in that it will provide us a “missing link” of information flow from DNA to complete 3D-structure. Not surprisingly, solution to this problem has applications outside the basic research in protein chemistry, such as design of drugs and enzymes.

The particular field which excites my interest is the division between the living and the non-living, as typified by, say, proteins, viruses, bacteria and the structure of chromosomes. The eventual goal, which is somewhat remote, is the description of these activities in terms of their structure, i.e. the spatial distribution of their constituent atoms, in so far as this may prove possible.

Francis Crick