Adaptively Biased Molecular Dynamics for Free Energy Calculations

We present an Adaptively Biased Molecular Dynamics (ABMD) method for the computation of the free energy surface of a reaction coordinate using non-equilibrium dynamics. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential, and is inspired by the metadynamics method. The ABMD method has several useful features, including a small number of control parameters, and an $O(t)$ numerical cost with molecular dynamics time $t$. The ABMD method naturally allows for extensions based on multiple walkers and replica exchange, where different replicas can have different temperatures and/or collective variables. This is beneficial not only in terms of the speed and accuracy of a calculation, but also in terms of the amount of useful information that may be obtained from a given simulation. The workings of the ABMD method are illustrated via a study of the folding of the Ace-GGPGGG-Nme peptide in a gaseous and solvated environment.Comment: Revised version to appear in Journal of Chemical Physic

Are Long-Range Structural Correlations Behind the Aggregration Phenomena of Polyglutamine Diseases?

We have characterized the conformational ensembles of polyglutamine peptides of various lengths (ranging from to ), both with and without the presence of a C-terminal polyproline hexapeptide. For this, we used state-of-the-art molecular dynamics simulations combined with a novel statistical analysis to characterize the various properties of the backbone dihedral angles and secondary structural motifs of the glutamine residues. For (i.e., just above the pathological length for Huntington's disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible -helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including - and -strands, and - and -hairpins. Most importantly, for we find that there exists a long-range correlation (ranging for at least residues) among the backbone dihedral angles of the Q residues. For polyglutamine peptides below the pathological length, the population of the extended strands and hairpins is considerably smaller, and the correlations are short-range (at most residues apart). Adding a C-terminal hexaproline to suppresses both the population of these rare motifs and the long-range correlation of the dihedral angles. We argue that the long-range correlation of the polyglutamine homopeptide, along with the presence of these rare motifs, could be responsible for its aggregation phenomena

Binding polymorphism in the DNA bound state of the Pdx1 homeodomain.

The subtle effects of DNA-protein recognition are illustrated in the homeodomain fold. This is one of several small DNA binding motifs that, in spite of limited DNA binding specificity, adopts crucial, specific roles when incorporated in a transcription factor. The homeodomain is composed of a 3-helix domain and a mobile N-terminal arm. Helix 3 (the recognition helix) interacts with the DNA bases through the major groove, while the N-terminal arm becomes ordered upon binding a specific sequence through the minor groove. Although many structural studies have characterized the DNA binding properties of homeodomains, the factors behind the binding specificity are still difficult to elucidate. A crystal structure of the Pdx1 homeodomain bound to DNA (PDB 2H1K) obtained previously in our lab shows two complexes with differences in the conformation of the N-terminal arm, major groove contacts, and backbone contacts, raising new questions about the DNA recognition process by homeodomains. Here, we carry out fully atomistic Molecular Dynamics simulations both in crystal and aqueous environments in order to elucidate the nature of the difference in binding contacts. The crystal simulations reproduce the X-ray experimental structures well. In the absence of crystal packing constraints, the differences between the two complexes increase during the solution simulations. Thus, the conformational differences are not an artifact of crystal packing. In solution, the homeodomain with a disordered N-terminal arm repositions to a partially specific orientation. Both the crystal and aqueous simulations support the existence of different stable binding conformers identified in the original crystallographic data with different degrees of specificity. We propose that protein-protein and protein-DNA interactions favor a subset of the possible conformations. This flexibility in DNA binding may facilitate multiple functions for the same transcription factor

Development of a “First Principles” Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficient

The development of a “first principles” water potential with flexible monomers (MB-pol) for molecular simulations of water systems from gas to condensed phases is described. MB-pol is built upon the many-body expansion of the intermolecular interactions, and the specific focus of this study is on the two-body term (V_2B) representing the full-dimensional intermolecular part of the water dimer potential energy surface. V_2B is constructed by fitting 40,000 dimer energies calculated at the CCSD­(T)/CBS level of theory and imposing the correct asymptotic behavior at long-range as predicted from “first principles”. The comparison of the calculated vibration–rotation tunneling (VRT) spectrum and second virial coefficient with the corresponding experimental results demonstrates the accuracy of the MB-pol dimer potential energy surface

Theoretical Modeling of Spin Crossover in Metal–Organic Frameworks: [Fe(pz)₂Pt(CN)₄] as a Case Study

Metal–organic frameworks (MOFs) with spin-crossover behavior are promising materials for applications in memory storage and sensing devices. A key parameter that characterizes these materials is the transition temperature <i>T</i>_1/2, defined as the temperature with equal populations of low-spin and high-spin species. In this study, we describe the development, implementation, and application of a novel hybrid Monte Carlo/molecular dynamics method that builds upon the Ligand Field Molecular Mechanics approach and enables the modeling of spin-crossover properties in bulk materials. The new methodology is applied to the study of a spin-crossover MOF with molecular formula [Fe­(pz)₂Pt­(CN)₄] (pz = pyrazine). The total magnetic moment of the material is determined as a function of the temperature from direct calculations of the relative equilibrium populations of both low-spin and high-spin states of each Fe­(II) center of the framework. The <i>T</i>_1/2 value, calculated from the temperature dependence of the magnetization curve, is in good agreement with the available experimental data. A comparison between the spin-crossover behavior of the isolated secondary building block of the framework and the bulk material is presented, which reveals the origin of the different spin-crossover properties of the isolated molecular system and corresponding MOF structure

Erratum: Development of a “First-Principles” Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficient

Erratum: Development of a “First-Principles” Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficien