Shaping up the protein folding funnel by local interaction: Lesson from a structure prediction study

Abstract

Predicting protein tertiary structure by folding-like simulations is one of the most stringent tests of how much we understand the principle of protein folding. Currently, the most successful method for folding-based structure prediction is the fragment assembly (FA) method. Here, we address why the FA method is so successful and its lesson for the folding problem. To do so, using the FA method, we designed a structure prediction test of ''chimera proteins.'' In the chimera proteins, local structural preference is specific to the target sequences, whereas nonlocal interactions are only sequence-independent compaction forces. We find that these chimera proteins can find the native folds of the intact sequences with high probability indicating dominant roles of the local interactions. We further explore roles of local structural preference by exact calculation of the HP lattice model of proteins. From these results, we suggest principles of protein folding: For small proteins, compact structures that are fully compatible with local structural preference are few, one of which is the native fold. These local biases shape up the funnel-like energy landscape.computational protein design ͉ energy landscape ͉ fragment assembly ͉ Go model ͉ SIMFOLD N atural proteins have the algorithm of finding the global minimum of their free energy surface within a biologically relevant timescale (1). One of the most stringent tests of how much we understand the algorithm may be to predict protein tertiary structures by simulating processes that are analogous to folding, which is often called de novo structure prediction. Recently, significant progress has been made in de novo structure prediction, in which the most successful method is the fragment assembly (FA) method developed by Baker and coworkers (2) and others (3-6). The FA method shows considerable promise for new fold targets of recent Critical Assessments of Techniques for Protein Structure Prediction (CASPs), the community-wide blind tests of structure prediction (7-11). In the FA method, the protocol is separated into two stages: First, we collect structural candidates for every short segment of the target sequence, retrieving them from the structural database. The second stage is to assemble͞fold these fragments for constructing tertiary structures that have low energies.Simple questions arose as to why the FA method is so successful and what we can learn about protein folding from the success of the FA method. According to Baker and coworkers (12,13), the FA method is based on the experimental observation that local sequence of a protein biases but does not uniquely decide its local structure. To what extent does the modest local bias influence tertiary structures generated? How is the FA method related to recently developed protein folding theory (14, 15)? In this work, we address these questions.For this purpose, we need structure prediction software that uses the FA method. Here, we use the in-house-developed software, SIMFOLD. SIMFOLD employs a coarse-grained protei...

Principles for Designing Ideal Protein Structures

“…This idea is supported by the fact that the relationships between secondary structure patterns and tertiary structure motifs we identified in simulations are also observed in native structures ( Fig. 1 and Supplementary Figs 1, 5, 7, 9 and 10); as in our design strategy, the disfavouring of the myriad alternative states may be achieved by naturally occurring sequences through the stabilization of local structures that disfavour nonnative topologies 31,32 .…”

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

“…The success of this method in different versions (e.g. successful prediction of native folds in chimera proteins (Chikenji et al 2006) strongly support the importance of early formed LIs in stabilizing the final fold of small proteins. In these models, the NLIs are assumed to have smaller role and can be non-specific.…”

“…On the basis of entropic considerations, Rose et al suggest that helix and strand formation will be guiding events in protein folding (Aurora et al 1997;Baldwin and Rose 1999a, b;Dadlez 1999). Folding prediction by the fragment assembly mechanism, which is based mainly on early formed LIs, was successfully used by many groups (Levitt 1992;Bowie and Eisenberg 1994;Simons et al 1997;Lee et al 1999;Chikenji et al 2006;Haspel et al 2003a, b). The success of this method in different versions (e.g.…”

The Fragment-based Consistency Score in Model Quality Assessment for De Novo Prediction of Protein Structures

“…Considerable advance has been made in techniques of template-based modeling (TBM) [1] [2], but a systematic and consistent method has not yet been developed to predict target proteins which do not have a suitable template. The latter problem is called de novo prediction, or template-free modeling (FM), which is the harder problem than TBM but is important for applications in wider problems of structural biology and for understanding principles of protein architecture [3][4] [5][6] [7]. In order to improve the de novo prediction technique, a helpful approach is to use methods of model quality assessment (MQA or QA).…”