Advances in enhanced sampling along adaptive paths of collective variables

Study of complex activated molecular transitions by molecular dynamics (MD) simulation can be a daunting task, especially when little knowledge is available on the reaction coordinate describing the mechanism of the process. Here, we assess the path-metadynamics enhanced sampling approach in combination with force field and ab initio [density functional theory (DFT)] MD simulations of conformational and chemical transitions that require three or more collective variables (CVs) to describe the processes. We show that the method efficiently localizes the average transition path of each process and simultaneously obtains the free energy profile along the path. The new multiple-walker implementation greatly speeds-up the calculation, with an almost trivial scaling of the number of parallel replicas. Increasing the dimensionality by expanding the set of CVs leads to a less than linear increase in the computational cost, as shown by applying the method to a conformational change in increasingly longer polyproline peptides. Combined with DFT-MD to model acid (de-)protonation in explicit water solvent, the transition path and associated free energy profile were obtained in less than 100 ps of simulation. A final application to hydrogen fuel production catalyzed by a hydrogenase enzyme showcases the unique mechanistic insight and chemical understanding that can be obtained from the average transition path. Published by AIP Publishing

Strong Reduction of the Chain Rigidity of Hyaluronan by Selective Binding of Ca2+ Ions

The biological functions of natural polyelectrolytes are strongly influenced by the presence of ions, which bind to the polymer chains and thereby modify their properties. Although the biological impact of such modifications is well recognized, a detailed molecular picture of the binding process and of the mechanisms that drive the subsequent structural changes in the polymer is lacking. Here, we study the molecular mechanism of the condensation of calcium, a divalent cation, on hyaluronan, a ubiquitous polymer in human tissues. By combining two-dimensional infrared spectroscopy experiments with molecular dynamics simulations, we find that calcium specifically binds to hyaluronan at millimolar concentrations. Because of its large size and charge, the calcium cation can bind simultaneously to the negatively charged carboxylate group and the amide group of adjacent saccharide units. Molecular dynamics simulations and single-chain force spectroscopy measurements provide evidence that the binding of the calcium ions weakens the intramolecular hydrogen-bond network of hyaluronan, increasing the flexibility of the polymer chain. We also observe that the binding of calcium to hyaluronan saturates at a maximum binding fraction of ∼10–15 mol %. This saturation indicates that the binding of Ca2+ strongly reduces the probability of subsequent binding of Ca2+ at neighboring binding sites, possibly as a result of enhanced conformational fluctuations and/or electrostatic repulsion effects. Our findings provide a detailed molecular picture of ion condensation and reveal the severe effect of a few, selective and localized electrostatic interactions on the rigidity of a polyelectrolyte chain

Traversing the free-energy pathways of intricate biomolecular processes:Enhanced simulation development and applications

Advances in the atomistic understanding of biomolecular structure and function come with wide applications in medicine, pharmacology and biomaterials, as well as with fundamental answers about the nature of living things. Such insight can in principle be brought by molecular dynamics (MD) simulations. However, even with nowadays vast computational resources, the timescales that are usually accessible in standard MD simulations cannot reliably sample many relevant biological processes, which occur either too slowly or too infrequently. We refer to this as the "rare event" problem. To overcome it, the MD community has devised an arsenal of enhanced sampling techniques, which deliver insight in the form of free-energy landscapes, projected on key descriptive molecular degrees of freedom, i.e. collective variables (CVs). Nonetheless, the computational cost scales exponentially with the number of CVs; meaning that complex transitions are typically out of grasp. In this thesis, we introduce novel path-based enhanced sampling strategies, and also combine them with other powerful simulation techniques; thus, advancing the capabilities to navigate complex molecular transitions. Our framework enables the study of intricate conformational and chemical changes in a variety of biomolecules; including oligopeptides, sensor proteins, DNA and polysaccharides. From each system, we extract fine mechanistic details, free energies and biological insights. We hope for these advancements to contribute to the long-term goals of biomolecular simulation; enabling the atomistic understanding of ever larger, more complex and realistic living systems

Atomistic insight into the kinetic pathways for Watson-Crick to Hoogsteen transitions in DNA

DNA predominantly contains Watson-Crick (WC) base pairs, but a non-negligible fraction of base pairs are in the Hoogsteen (HG) hydrogen bonding motif at any time. In HG, the purine is rotated similar to 180 degrees relative to the WC motif. The transitions between WC and HG may play a role in recognition and replication, but are difficult to investigate experimentally because they occur quickly, but only rarely. To gain insight into the mechanisms for this process, we performed transition path sampling simulations on a model nucleotide sequence in which an AT pair changes from WC to HG. This transition can occur in two ways, both starting with loss of hydrogen bonds in the base pair, followed by rotation around the glycosidic bond. In one route the adenine base converts from WC to HG geometry while remaining entirely within the double helix. The other route involves the adenine leaving the confines of the double helix and interacting with water. Our results indicate that this outside route is more probable. We used transition interface sampling to compute rate constants and relative free energies for the transitions between WC and HG. Our results agree with experiments, and provide highly detailed insights into the mechanisms of this important process