Collective many-body van der Waals interactions in molecular systems

Robert A. DiStasio, Jr., O. Anatole von Lilienfeld, and Alexandre Tkatchenko

Van der Waals (vdW) interactions are ubiquitous in molecules and condensed matter, and play a crucial role in determining the structure, stability, and function for a wide variety of systems. The accurate prediction of these interactions from first principles is a substantial challenge because they are inherently quantum mechanical phenomena that arise from correlations between many electrons within a given molecular system. We introduce an efficient method that accurately describes the nonadditive many-body vdW energy contributions arising from interactions that cannot be modeled by an effective pairwise approach, and demonstrate that such contributions can significantly exceed the energy of thermal fluctuations—a critical accuracy threshold highly coveted during molecular simulations—in the prediction of several relevant properties. Cases studied include the binding affinity of ellipticine, a DNA-intercalating anticancer agent, the relative energetics between the A- and B-conformations of DNA, and the thermodynamic stability among competing paracetamol molecular crystal polymorphs. Our findings suggest that inclusion of the many-body vdW energy is essential for achieving chemical accuracy and therefore must be accounted for in molecular simulations.

DOI

Journal: Proceedings of the National Academy of Sciences

Direct observation of a force-induced switch in the anisotropic mechanical unfolding pathway of a protein

Bharat Jagannathan, Phillip J. Elms, Carlos Bustamante, and Susan Marqusee

Many biological processes generate force, and proteins have evolved to resist and respond to tension along different force axes. Single-molecule force spectroscopy allows for molecular insight into the behavior of proteins under force and the mechanism of protein folding in general. Here, we have used src SH3 to investigate the effect of different pulling axes under the low-force regime afforded by an optical trap. We find that this small cooperatively folded protein shows an anisotropic response to force; the protein is more mechanically resistant to force applied along a longitudinal axis compared to force applied perpendicular to the terminal β strand. In the longitudinal axis, we observe an unusual biphasic behavior revealing a force-induced switch in the unfolding mechanism suggesting the existence of two parallel unfolding pathways. A site-specific variant can selectively affect one of these pathways. Thus, even this simple two-state protein demonstrates a complex mechanical unfolding trajectory, accessing multiple unfolding pathways under the low-force regime of the optical trap; the specific unfolding pathway depends on the perturbation axis and the applied force.

DOI

Journal: Proceedings of the National Academy of Sciences

OpenFovea: open-source AFM data processing software

Charles Roduit, Bhaskar Saha, Livan Alonso-Sarduy, Andrea Volterra, Giovanni Dietler, and Sandor Kasas

The atomic force microscope (AFM) is often used to detect specific molecules on the surfaces of specimens and to measure a specimen's mechanical properties. This information can be deduced from the force-distance curves generated by the deflection of the cantilever as it approaches, indents and recedes from the sample. Force-volume images can be generated from a series of successive force-distance curves recorded while scanning an area of the specimen. This imaging mode has been used since 1997 to image, among others, proteins at molecular resolution, molecular patterns, bacteria, fungi and living cells. Algorithms for processing force-volume data files have been published3, but there is no universal ready-to-use software for analysis of force-distance curves, and investigators must develop their own custom software.

DOI

Journal: Nature Methods

Key stabilizing elements of protein structure identified through pressure and temperature perturbation of its hydrogen bond network

Lydia Nisius, and Stephan Grzesiek

Hydrogen bonds are key constituents of biomolecular structures, and their response to external perturbations may reveal important insights about the most stable components of a structure. NMR spectroscopy can probe hydrogen bond deformations at very high resolution through hydrogen bond scalar couplings (HBCs). However, the small size of HBCs has so far prevented a comprehensive quantitative characterization of protein hydrogen bonds as a function of the basic thermodynamic parameters of pressure and temperature. Using a newly developed pressure cell, we have now mapped pressure- and temperature-dependent changes of 31 hydrogen bonds in ubiquitin by measuring HBCs with very high precision. Short-range hydrogen bonds are only moderately perturbed, but many hydrogen bonds with large sequence separations (high contact order) show greater changes. In contrast, other high-contact-order hydrogen bonds remain virtually unaffected. The specific stabilization of such topologically important connections may present a general principle with which to achieve protein stability and to preserve structural integrity during protein function.

DOI

Journal: Nature Chemistry

Experimental free-energy measurements of kinetic molecular states using fluctuation theorems

Anna Alemany, Alessandro Mossa, Ivan Junier, and Felix Ritort

Recent advances in non-equilibrium statistical mechanics and single-molecule technologies have made it possible to use irreversible work measurements to extract free-energy differences associated with the mechanical (un)folding of molecules. To date, free-energy recovery has been focused on native (or equilibrium) molecular states, but free-energy measurements of kinetic states have remained unexplored. Kinetic states are metastable, finite-lifetime states that are generated dynamically, and play important roles in diverse physical processes. In biophysics, there are many examples in which these states determine the fate of molecular reactions, including protein binding, enzymatic reactions, as well as the formation of transient intermediate states during molecular-folding processes. Here we demonstrate that it is possible to obtain free energies of kinetic states by applying extended fluctuation relations, using optical tweezers to mechanically unfold and refold deoxyribonucleic acid (DNA) structures exhibiting intermediate and misfolded kinetic states.

DOI

Journal: Nature Physics

A Whole-Cell Computational Model Predicts Phenotype from Genotype

Jonathan R. Karr, Jayodita C. Sanghvi, Derek N. Macklin, Miriam V. Gutschow, Jared M. Jacobs, Benjamin Bolival Jr., Nacyra Assad-Garcia, John I. Glass, Markus W. Covert

Understanding how complex phenotypes arise from individual molecules and their interactions is a primary challenge in biology that computational approaches are poised to tackle. We report a whole-cell computational model of the life cycle of the human pathogen Mycoplasma genitalium that includes all of its molecular components and their interactions. An integrative approach to modeling that combines diverse mathematics enabled the simultaneous inclusion of fundamentally different cellular processes and experimental measurements. Our whole-cell model accounts for all annotated gene functions and was validated against a broad range of data. The model provides insights into many previously unobserved cellular behaviors, including in vivo rates of protein-DNA association and an inverse relationship between the durations of DNA replication initiation and replication. In addition, experimental analysis directed by model predictions identified previously undetected kinetic parameters and biological functions. We conclude that comprehensive whole-cell models can be used to facilitate biological discovery.

DOI

Journal: Cell

Interaction landscape of membrane-protein complexes in Saccharomyces cerevisiae

Mohan Babu et. al

Macromolecular assemblies involving membrane proteins (MPs) serve vital biological roles and are prime drug targets in a variety of diseases1. Large-scale affinity purification studies of soluble-protein complexes have been accomplished for diverse model organisms, but no global characterization of MP-complex membership has been described so far. Here we report a complete survey of 1,590 putative integral, peripheral and lipid-anchored MPs from Saccharomyces cerevisiae, which were affinity purified in the presence of non-denaturing detergents. The identities of the co-purifying proteins were determined by tandem mass spectrometry and subsequently used to derive a high-confidence physical interaction map encompassing 1,726 membrane protein–protein interactions and 501 putative heteromeric complexes associated with the various cellular membrane systems. Our analysis reveals unexpected physical associations underlying the membrane biology of eukaryotes and delineates the global topological landscape of the membrane interactome.

DOI

Journal: Nature