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Energy Landscape in Protein Folding and Unfolding Energy landscape in protein folding and unfolding Francesco Mallamacea,b,c,1, Carmelo Corsaroa,d, Domenico Mallamacee, Sebastiano Vasid, Cirino Vasia, Piero Baglionif, Sergey V. Buldyrevg, Sow-Hsin Chenb, and H. Eugene Stanleyc,1 aCNR-Istituto per i Processi Chimico Fisici Messina, I-98166 Messina, Italy; bDepartment of Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; cCenter for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215; dDipartimento di Fisica e di Scienze della Terra, Università di Messina, I-98166 Messina, Italy; eConsorzio per lo Sviluppo dei Sistemi a Grande Interfase, Unità di Catania, I-95125 Catania, Italy; fDipartimento di Chimica, Università di Firenze and Consorzio per lo Sviluppo dei Sistemi a Grande Interfase, I-50019 Florence, Italy; and gDepartment of Physics, Yeshiva University, New York, NY 10033 Contributed by H. Eugene Stanley, December 22, 2015 (sent for review March 17, 2015; reviewed by Anders Nilsson and Michele Parrinello) We use 1H NMR to probe the energy landscape in the protein fold- simulation (9, 10) and different experimental techniques (11–16). ing and unfolding process. Using the scheme ⇄ reversible unfolded Whereas MD simulations directly model peptide conformational (intermediate) → irreversible unfolded (denatured) state, we study transitions in terms of the energy landscape, experiments supply the thermal denaturation of hydrated lysozyme that occurs when useful but limited information, revealing some details in the the temperature is increased. Using thermal cycles in the range structure and the collective dynamics of protein, both dry and in 295 < T < 365 K and following different trajectories along the protein solution. Examples of this include the spectroscopic techniques energy surface, we observe that the hydrophilic (the amide NH) and (e.g., NMR, neutron, X-ray, Raman, and FTIR) that supply data hydrophobic (methyl CH3 and methine CH) peptide groups evolve on structure and dynamical modes of the protein, and the and exhibit different behaviors. We also discuss the role of water calorimetric measurements that follow the reversible folding– and hydrogen bonding in the protein configurational stability. unfolding as far as irreversible denaturation (9, 10). The protein dynamics have been studied from the glass state in the deep protein folding | proton NMR | energy landscape | hydration water supercooled regime (T < 200 K) to the completely denatured state (T ’ 350 K) by proving the essential role of the hydration n intriguing problem of statistical physics concerns the water. As for bulk water, hydrogen bond (HB) interactions Aevolutionary pathways that molecular systems follow as they strongly determine the properties of these systems, for which SCIENCES form mesoscale structures and exhibit new functional behaviors water is not simply a solvent but is also an integral and active APPLIED PHYSICAL (1). An example of this problem is the self-organization of bio- component, i.e., it is itself an important “biomolecule” that plays systems that evolve from basic molecules. This challenging sub- both a dynamic and structural role (17). Hence, HB interactions ject is studied by using a variety of theoretical methods (2–4). are the key to understanding water’s properties and how water The free-energy landscape model is nowadays the most used to functions in biological environments (18). describe such phenomena and especially the aging of the protein Among the different experimental methods, calorimetry, by folding mechanism (1, 5, 6), i.e., the way in which proteins fold to monitoring the process reaction rates, focuses directly the energetic their native state and then unfold (protein denaturation) (6, 7). properties of the hydrated proteins folding–unfolding mechanism BIOPHYSICS AND The model is based on the idea that in complex materials and and measures the enthalpy and entropy behaviors. Unlike common COMPUTATIONAL BIOLOGY systems there are many thermodynamical configurations in which chemical reaction rates, which increase as the temperature is in- the free-energy surface exhibits a number of local minima sepa- creased, the rate constant of the protein folding reaction initially rated by barriers, i.e., as the system explores its phase space the increases on increasing T, by following an Arrhenius law goes to a trajectory of its evolution is an alternating sequence of local maximum, and then decreases as the temperature continues to energy minima and saddle points (transition states), which are increase (19). This latter situation is also well-described in MD associated with the positions of all of the system particles. A simulations (20). The activation enthalpy is thus T-dependent and trajectory thus specifies the path of the system as it evolves by the corresponding protein specific heat, CPðTÞ, exhibits large moving across its energy landscape. A peptide is a linear chain of amino acids, and globular pro- Significance teins are polypeptide chains that fold into their native confor- mation. During the folding process a polypeptide undergoes many conformational changes and there is a significant decrease Protein folding represents an open question in science, and the in the system configurational entropy as the native state is free-energy landscape framework is one way to describe it. In particular, the role played by water in the processes is of spe- approached. To understand folding we focus on how proteins – search conformational space. The process is accompanied by cial interest. To clarify these issues we study, during folding many microscopic reactions, the nature of which is determined unfolding, the temperature evolution of the magnetization for by the specifics of the energy surface. Thus, the characteristics of hydrophilic and hydrophobic groups of hydrated lysozyme the energy surface of a polypeptide chain are the key to a quan- using NMR spectroscopy. Our findings confirm the validity of titative understanding of folding. Although the degrees of freedom the theoretical scenario of a process dominated by different energetic routes, also explaining the water role in the protein of a polypeptide chain allow an enormously large number of configuration stability. We also highlight that the protein native possible configurations, “constraints” on the energy decrease these state limit is represented by the water singular temperature that configurations visited in the folding reaction to a limited number characterizes its compressibility and expansivity and is the origin (8). Understanding the free-energy surface (“landscape”)enables of the thermodynamical anomalies of its liquid state. us to understand the folding process. A balance between the potential energy and the configurational entropy leads to a free- Author contributions: F.M., C.C., P.B., S.V.B., and H.E.S. designed research; F.M., C.C., D.M., energy barrier that generates the two-state folding behavior usu- S.V., and C.V. performed research; F.M., D.M., S.V., P.B., S.V.B., and S.-H.C. analyzed data; ally observed in small proteins. The potential energy decreases as and F.M., C.C., and H.E.S. wrote the paper. the native state is approached and favors folding, but decreasing Reviewers: A.N., SLAC National Accelerator Laboratory; and M.P., ETH Zurich. the entropy of the configuration is unfavorable to folding. The authors declare no conflict of interest. The thermodynamics and kinetics of folding and unfolding 1To whom correspondence may be addressed. Email: [email protected] or have been intensively studied by molecular dynamics (MD) [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1524864113 PNAS | March 22, 2016 | vol. 113 | no. 12 | 3159–3163 Downloaded by guest on September 25, 2021 changes: first it increases with T, reaches a maximum, and then precisely, to quantify the behavior of the protein hydrophilic (the decreases. Hence a CPðTÞ plot against T exhibits an endothermic amide NH) and hydrophobic (methyl and methine) groups, during peak whose area is related to the enthalpy of transformation of the folding–unfolding process, we use as control variable the the protein. Such a behavior is also strongly influenced by the temperature, which slows the process kinetics to many hours. protein hydrophobic side chains and hydration water (19, 21, 22). The goal is to determine the topography of the protein energy NMR spectroscopy instead can be used to follow folding (or landscape by following different trajectories along the energy unfolding) processes by probing interactions as they form at surface. This allows us also to consider explicitly the role of water the level of individual residues, and to compare the findings and hydrogen bonding in protein configurational stability. obtained with simulations (13, 23–25). NMR studies involve in- vestigation of the equilibrium conversion between native and Results denatured states resulting from a protein being subjected to heat, Thermal denaturation of lysozyme occurs according to the extremes of pH, or chemical denaturants. The kinetics of the scheme, native state (N) ⇄ reversible unfolded (intermediate) process may limit the observations. If the folding occurs on a state (RU) → irreversible unfolded (denatured) state (IU); N ⇄ time scale for which spectra can be measured and recorded se- RU → IU (21, 22). This is consistent with the general view that quentially, the spectral changes accompanying the reaction can the first step in the denaturation of small one-domain globular be
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