Abstract
Structural elements inserted in proteins are essential to define folding/unfolding mechanisms and partner recognition events governing signaling processes in living organisms. Here, we present an original approach to model the folding mechanism of these structural elements. Our approach is based on the exploitation of local, sequence-dependent structural information encoded in a database of three-residue fragments extracted from a large set of high-resolution experimentally determined protein structures. The computation of conformational transitions leading to the formation of the structural elements is formulated as a discrete path search problem using this database. To solve this problem, we propose a heuristically-guided depth-first search algorithm. The domain-dependent heuristic function aims at minimizing the length of the path in terms of angular distances, while maximizing the local density of the intermediate states, which is related to their probability of existence. We have applied the strategy to two small synthetic polypeptides mimicking two common structural motifs in proteins. The folding mechanisms extracted are very similar to those obtained when using traditional, computationally expensive approaches. These results show that the proposed approach, thanks to its simplicity and computational efficiency, is a promising research direction.
Highlights
Introduction and Related WorkProteins are bio-macro-molecules that perform essential functions in living organisms
The results reported in this paper are consistent with respect to those described in related literature, and already show the interest of the proposed approach, which is extremely fast when compared with currently-used computational methods based on molecular dynamics (MD) simulations [36]
We present results obtained with the proposed approach for the analysis of the folding process of two synthetic mini-proteins, Chignolin and DS119, which were designed to fold into structural motifs present in natural proteins
Summary
Proteins are bio-macro-molecules that perform essential functions in living organisms. They are composed of chains of amino acid residues (in the following, we will use the word residue to refer to an amino acid residue), called polypeptide chains, that, in most of the cases, fold into functional three-dimensional structures. The amino acid sequence determines the three-dimensional structure and its stability. The sequence determines the frequency and the transition rate between unfolded and folded states. Understanding the mechanisms of protein folding and unfolding as a function of the amino acid sequence is of paramount importance, giving their relevance in biological processes [1]. Numerous diseases are related to the inability of proteins to fold correctly or to form insoluble amyloidogenic aggregates due to mutations or metabolic deregulation [2,3]
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