Entropy, Fluctuations, and Disordered Proteins

Entropy should directly reflect the extent of disorder in proteins. By clustering structurally related proteins and studying the multiple-sequence-alignment of the sequences of these clusters, we were able to link between sequence, structure, and disorder information. We introduced several parameters as measures of fluctuations at a given MSA site and used these as representative of the sequence and structure entropy at that site. In general, we found a tendency for negative correlations between disorder and structure, and significant positive correlations between disorder and the fluctuations in the system. We also found evidence for residue-type conservation for those residues proximate to potentially disordered sites. Mutation at the disorder site itself appear to be allowed. In addition, we found positive correlation for disorder and accessible surface area, validating that disordered residues occur in exposed regions of proteins. Finally, we also found that fluctuations in the dihedral angles at the original mutated residue and disorder are positively correlated while dihedral angle fluctuations in spatially proximal residues are negatively correlated with disorder. Our results seem to indicate permissible variability in the disordered site, but greater rigidity in the parts of the protein with which the disordered site interacts. This is another indication that disordered residues are involved in protein function

Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function. Hypotheses and a comprehensive review

During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into ‘cumulus-type’, i.e., those similar to puffy (white) clouds, and ‘stratus-type’, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an ‘energy transfer’ mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by ‘multi-trajectories’; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach ‘rarely visited’ but functionally-related states. We also show the role of disorder in ‘spatial games’ of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks

Buried and accessible surface area control intrinsic protein flexibility

Proteins experience a wide variety of conformational dynamics that can be crucial for facilitating their diverse functions. How is the intrinsic flexibility required for these motions encoded in their three-dimensional structures? Here, the overall flexibility of a protein is demonstrated to be tightly coupled to the total amount of surface area buried within its fold. A simple proxy for this, the relative solvent accessible surface area (Arel), therefore shows excellent agreement with independent measures of global protein flexibility derived from various experimental and computational methods. Application of Arel on a large scale demonstrates its utility by revealing unique sequence and structural properties associated with intrinsic flexibility. In particular, flexibility as measured by Arel shows little correspondence with intrinsic disorder, but instead tends to be associated with multiple domains and increased {\alpha}- helical structure. Furthermore, the apparent flexibility of monomeric proteins is found to be useful for identifying quaternary structure errors in published crystal structures. There is also a strong tendency for the crystal structures of more flexible proteins to be solved to lower resolutions. Finally, local solvent accessibility is shown to be a primary determinant of local residue flexibility. Overall this work provides both fundamental mechanistic insight into the origin of protein flexibility and a simple, practical method for predicting flexibility from protein structures.Comment: 36 pages, 11 figures, author's manuscript, accepted for publication in Journal of Molecular Biolog

Melting of Single Lipid Components in Binary Lipid Mixtures: A Comparison between FTIR Spectroscopy, DSC and Monte Carlo Simulations

Monte Carlo (MC) Simulations, Differential Scanning Calorimetry (DSC) and Fourier Transform InfraRed (FTIR) spectroscopy were used to study the melting behavior of single lipid components in two-component membranes of 1,2-Dimyristoyl-D54-sn-Glycero-3-Phosphocholine (DMPC-d54) and 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC). Microscopic information on the temperature dependent melting of the single lipid species could be investigated using FTIR. The microscopic behavior measured could be well described by the results from the MC simulations. These simulations also allowed to calculate heat capacity profiles as determined with DSC. These ones provide macroscopic information about melting enthalpies and entropy changes which are not accessible with FTIR. Therefore, the MC simulations allowed us to link the two different experimental approaches of FTIR and DSC.Comment: 12 pages, 5 figures, corrected typo in table 1 in which previously it said Tm,1 instead of Tm,

Free Energy Self-Averaging in Protein-Sized Random Heteropolymers

Current theories of heteropolymers are inherently macrpscopic, but are applied to folding proteins which are only mesoscopic. In these theories, one computes the averaged free energy over sequences, always assuming that it is self-averaging -- a property well-established only if a system with quenched disorder is macroscopic. By enumerating the states and energies of compact 18, 27, and 36mers on a simplified lattice model with an ensemble of random sequences, we test the validity of the self-averaging approximation. We find that fluctuations in the free energy between sequences are weak, and that self-averaging is a valid approximation at the length scale of real proteins. These results validate certain sequence design methods which can exponentially speed up computational design and greatly simplify experimental realizations.Comment: 4 pages, 3 figure

Side-chain conformational changes upon protein-protein association

Conformational changes upon protein-protein association are the key element of the binding mechanism. The study presents a systematic large-scale analysis of such conformational changes in the side chains. The results indicate that short and long side chains have different propensities for the conformational changes. Long side chains with three or more dihedral angles are often subject to large conformational transition. Shorter residues with one or two dihedral angles typically undergo local conformational changes not leading to a conformational transition. The relationship between the local readjustments and the equilibrium fluctuations of a side chain around its unbound conformation is suggested. Most of the side chains undergo larger changes in the dihedral angle most distant from the backbone. The amino acids with symmetric aromatic (Phe and Tyr) and charged (Asp and Glu) groups show the opposite trend where the near-backbone dihedral angles change the most. The frequencies of the core-to-surface interface transitions of six nonpolar residues and Tyr exceed the frequencies of the opposite, surface-to-core transitions. The binding increases both polar and nonpolar interface areas. However, the increase of the nonpolar area is larger for all considered classes of protein complexes. The results suggest that the protein association perturbs the unbound interfaces to increase the hydrophobic forces. The results facilitate better understanding of the conformational changes in proteins and suggest directions for efficient conformational sampling in docking protocols.Comment: 21 pages, 6 figure