Conservation of coevolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone.

Protein-protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue coevolution provides accurate predictions of heterodimeric protein interfaces from sequence information.

Epigenomic Co-localization and Co-evolution Reveal a Key Role for 5hmC as a Communication Hub in the Chromatin Network of ESCs.

Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation.

From residue coevolution to protein conformational ensembles and functional dynamics.

The analysis of evolutionary amino acid correlations has recently attracted a surge of renewed interest, also due to their successful use in de novo protein native structure prediction. However, many aspects of protein function, such as substrate binding and product release in enzymatic activity, can be fully understood only in terms of an equilibrium ensemble of alternative structures, rather than a single static structure. In this paper we combine coevolutionary data and molecular dynamics simulations to study protein conformational heterogeneity.

Large-Scale Conformational Transitions and Dimerization Are Encoded in the Amino-Acid Sequences of Hsp70 Chaperones.

Hsp70s are a class of ubiquitous and highly conserved molecular chaperones playing a central role in the regulation of proteostasis in the cell. Hsp70s assist a myriad of cellular processes by binding unfolded or misfolded substrates during a complex biochemical cycle involving large-scale structural rearrangements. Here we show that an analysis of coevolution at the residue level fully captures the characteristic large-scale conformational transitions of this protein family, and predicts an evolutionary conserved-and thus functional-homo-dimeric arrangement.

Energy-Driven Undocking (EDU-HREM) in Solute Tempering Replica Exchange Simulations.

We present a new computational strategy for calculating the absolute binding free energy for protein ligand association in the context of atomistic simulation in explicit solvent. The method is based on an appropriate definition of a solute tempering scheme enforced via Hamilton replica exchange method (HREM). The definition of "solute" includes both the ligand and the active site, with the remainder of the systems defined as "solvent".

Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2 kinase domain.

Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) is a receptor tyrosine kinase involved in the angiogenesis process and regarded as an interesting target for the design of anticancer drugs. Its activation/inactivation mechanism is related to conformational changes in its cytoplasmatic kinase domain, involving first among all the αC-helix in N-lobe and the A-loop in C-lobe. Affinity of inhibitors for the active or inactive kinase form could dictate the open or closed conformation of the A-loop, thus making the different conformations of the kinase domain receptor (KDR) domain different drug targets in drug discovery.

Intraligand hydrophobic interactions rationalize drug affinities for peptidyl-prolyl cis-trans isomerase protein.

The conformational landscape of three FK506-related drugs with disparate inhibition constants is determined in bulk solution using a replica exchange simulation method with solute torsional tempering. Energetic fitness of important drug conformations with respect to the FKBP12 protein is evaluated by molecular mechanics. Results show that the experimental affinity toward peptidyl-prolyl cis-trans isomerase protein (FKBP12) of the analyzed ligands appears to be positively correlated to the observed population of specific chair structures of the drug piperidinic ring in bulk solution.

Conformational structure of the MOG-derived peptide 101-108 in solution.

One of the most important targets in the autoimmune attack in experimental autoimmune encephalomyielitis is the myelin oligodendrocyte glycoprotein (MOG). The complex with demyelinating 8-18C5 antibody was recently resolved by X-ray crystallography, showing a remarkable adhesion of the 101-108 MOG subsequence to the heavy chain of the autoantibody. In this study, we have determined, using replica exchange molecular dynamics methods, the structure of the MOG-derived peptide 101-108 in solution at ambient conditions.

Free energy reconstruction in bidirectional force spectroscopy experiments: the effect of the device stiffness.

In force spectroscopy single-molecule experiments, an individual molecule, usually a polymer, is mechanically stretched by means of an externally controlled driving potential. Typically, the stiffness of this potential is much smaller than the stiffness of the potential of mean force along the molecular extension coordinate. Here we discuss how such a disparity alters the free energy and the reversibility of the driven system, with respect to the pristine molecular system under examination.

Fragment 101-108 of myelin oligodendrocyte glycoprotein: a possible lead compound for multiple sclerosis.

Multiple Sclerosis (MS) is a highly invalidating autoimmune disease of the central nervous system, leading to progressive paralysis and, sometimes, to premature death. One of the potential targets of the autoimmune reaction is the myelin protein MOG (Myelin Oligodendrocyte Glycoprotein). Since the 101-108 fragment of MOG plays a key role in the interaction with the MS-autoantibody 8-18C5, we performed an analysis of the equilibrium conformations of this peptide using the Replica Exchange Molecular Dynamics technique in conjunction with the Generalized Born continuum solvent model.

ORAC: a molecular dynamics simulation program to explore free energy surfaces in biomolecular systems at the atomistic level.

We present the new release of the ORAC engine (Procacci et al., Comput Chem 1997, 18, 1834), a FORTRAN suite to simulate complex biosystems at the atomistic level. The previous release of the ORAC code included multiple time steps integration, smooth particle mesh Ewald method, constant pressure and constant temperature simulations.

Calculation of the potential of mean force from nonequilibrium measurements via maximum likelihood estimators.

We present an approach to the estimate of the potential of mean force along a generic reaction coordinate based on maximum likelihood methods and path-ensemble averages in systems driven far from equilibrium. Following similar arguments, various free energy estimators can be recovered, all providing comparable computational accuracy. The method, applied to the unfolding process of the alpha -helix form of an alanine decapeptide, gives results in good agreement with thermodynamic integration.

Thermodynamics of stacking interactions in proteins.

Using a database of 6166 experimental structures taken from the Protein Data Bank, we have studied pair interactions between planar residues (Phe, Tyr, His, Arg, Glu and Asp) in proteins, known as pi-pi interactions. On the basis of appropriate coordinates defining the mutual arrangement of two residues, we have calculated 2-D potentials of mean force aimed at determining the stability of the most probable structures for aromatic-aromatic, aromatic-cation and aromatic-anion bound pairs. Our analysis reveals the thermodynamic relevance and the ubiquity of stacked complexes in proteins.

Generalization of the Jarzynski and Crooks nonequilibrium work theorems in molecular dynamics simulations.

The Jarzynski identity [C. Jarzynski, Phys. Rev.

Numerical verification of the generalized Crooks nonequilibrium work theorem for non-Hamiltonian molecular dynamics simulations.

The generalized Crooks theorem (GCT) for deterministic non-Hamiltonian molecular dynamics simulations [Phys. Rev. E 75, 050101 (2007)] connects the probabilities of nonequilibrium realizations switching the system between two thermodynamic states, to the partition functions of these states.

Recovering the Crooks equation for dynamical systems in the isothermal-isobaric ensemble: a strategy based on the equations of motion.

The Crooks equation [Eq. (10) in J. Stat.

Crooks equation for steered molecular dynamics using a Nosé-Hoover thermostat.

The Crooks equation [Eq. (10) in J. Stat.

Self-healing umbrella sampling: a non-equilibrium approach for quantitative free energy calculations.

We propose a new approach for the umbrella sampling method in molecular dynamics simulations of complex systems. An accelerated sampling of the slow degrees of freedom is achieved by generating a single self-adaptive trajectory that tends to span uniformly the reaction coordinate using a time dependent bias potential derived from the preceding history of the system. To show the convergent behavior and the efficiency of the method, we present the free energy surface of alanine dipeptide in water as a function of the backbone dihedral angles.