A Coarse-Grained Approach to Protein Design: Learning from Design to Understand Folding

Coluzza, Ivan

doi:10.1371/journal.pone.0020853

Cited by 47 publications

(107 citation statements)

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“…We demonstrate how the cold-and P-denaturation mechanisms can emerge as a competition between different free energy contributions coming from water, one from hydration water and another from bulk water. Moreover, we show how changes in the protein sequence affect the hydration water properties and, in turn, the stability of the protein folded staterelevant information in protein design [27].The many-body water model adopts a coarse-grain (CG) representation of the water coordinates by partitioning the available volume V into a fixed number N 0 of cells, each with volume v ≡ V=N 0 ≥ v 0 , where v 0 is the water excluded volume. Each cell accommodates at most one molecule with the average O-O distance between nearest neighbor (NN) water molecules given by r ¼ v 1=3 .…”

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confidence: 99%

“…However, the interpretations of the mechanism are still controversial [8,[24][25][26][27][28][29][30][31][32][33][34][35][36][37]. High-T denaturation is easily understood in terms of thermal fluctuations that disrupt the compact protein conformation: the open protein structure increases the entropy S minimizing the global Gibbs free energy G ≡ H − TS, where H is the total enthalpy.…”

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confidence: 99%

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Contribution of Water to Pressure and Cold Denaturation of Proteins

2015

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The mechanisms of cold and pressure denaturation of proteins are matter of debate and are commonly understood as due to water-mediated interactions. Here, we study several cases of proteins, with or without a unique native state, with or without hydrophilic residues, by means of a coarse-grain protein model in explicit solvent. We show, using Monte Carlo simulations, that taking into account how water at the protein interface changes its hydrogen bond properties and its density fluctuations is enough to predict protein stability regions with elliptic shapes in the temperature-pressure plane, consistent with previous theories. Our results clearly identify the different mechanisms with which water participates to denaturation and open the perspective to develop advanced computational design tools for protein engineering. DOI: 10.1103/PhysRevLett.115.108101 PACS numbers: 87.15.Cc, 87.15.A-, 87.15.kr Water plays an essential role in driving the folding of a protein and in stabilizing the tertiary protein structure in its native state [1,2]. Proteins can denaturate-unfolding their structure and losing their activity-as a consequence of changes in the environmental conditions. Experimental data show that for many proteins the native folded state is stable in a limited range of temperatures T and pressures P [3][4][5][6][7][8] and that partial folding is T modulated also in "intrinsically disordered proteins" [9]. By hypothesizing that proteins have only two different states, folded (f) and unfolded (u), and that the f⟷u process is reversible at any moment, Hawley proposed a theory [10] that predicts a close stability region (SR) with an elliptic shape in the T-P plane, consistent with the experimental data [11].Cold and P denaturation of proteins have been related to the equilibrium properties of the hydration water [12][13][14][15][16][17][18][19][20][21][22][23]. However, the interpretations of the mechanism are still controversial [8,[24][25][26][27][28][29][30][31][32][33][34][35][36][37]. High-T denaturation is easily understood in terms of thermal fluctuations that disrupt the compact protein conformation: the open protein structure increases the entropy S minimizing the global Gibbs free energy G ≡ H − TS, where H is the total enthalpy. High-P unfolding can be explained by the loss of internal cavities in the folded states of proteins [36], while denaturation at negative P has been experimentally observed [38] and simulated [38,39] recently. Cold and P unfolding can be thermodynamically justified assuming an enthalpic gain of the solvent upon the denaturation process, without specifying the origin of this gain from molecular interactions [40]. Here, we propose a molecular-interactions model for proteins solvated by explicit water, based on the "many-body" water model [32,[41][42][43][44][45]. We demonstrate how the cold-and P-denaturation mechanisms can emerge as a competition between different free energy contributions coming from water, one from hydration water and another from bulk water. Moreover, we sh...

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Contribution of Water to Pressure and Cold Denaturation of Proteins

2015

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“…Here, r is the distance between the two anchoring patches and κ = 5 k B T R The model colloidal polymer studied here is based on the caterpillar model [5]. Accordingly, the colloidal particles interact pairwise via a smoothed square well pair potential…”

Section: A Modelmentioning

confidence: 99%

“…As we aim to imitate the designability property of natural proteins, we based the identity mutations move on the design scheme successfully used in protein studies [5]. As in the conventional Metropolis scheme, the acceptance of such trial moves depends on the ratio of the Boltzmann weights of the new and old states for each temperature T [18].…”

Section: B P1mentioning

confidence: 99%

The configurational space of colloidal patchy polymers with heterogeneous sequences

Coluzza

Dellago²

2012

J. Phys.: Condens. Matter

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In this work we characterize the configurational space of a short chain of colloidal particles as function of the range of directional and heterogeneous isotropic interactions. The individual particles forming the chain are colloids decorated with patches that act as interaction sites between them. We show, using computer simulations, that it is possible to sample the relative probability of occurrence of a structure with a sequence in the space of all possible realizations of the chain. The results presented here represent a first attempt to map the space of possible configurations that a chain of colloidal particles may adopt. Knowledge of such a space is crucial for a possible application of colloidal chains as models for designable self-assembling systems.

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“…This difficulty could explain why, to the * Email: ivan.coluzza@univie.ac.at best of our knowledge, the folding of Go and designed proteins have not been so far compared. In this regard, we have recently introduced the Caterpillar model [39], which we extended to perform both quantitative protein design and folding [40], making the perfect tool for this study. It is important to stress that, regardless of the accuracy of the model, the comparison between the designed and the Golike models is valid even if the natural folding landscape of the tested proteins looks different from the one predicted by the Caterpillar model.…”

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confidence: 99%