Thermodynamics of unstable DNA structures from the kinetics of the microgene PCR

The microgene polymerization reaction (MPR) generates head-to-tail tandem repeats from homoduplexes (HDs). In MPR initiation, one HD putatively aligns two others in the proximity required to form a nucleation complex, thus allowing the DNA polymerase to skip the intertemplate gap and generate an initial doublet (ID) prone to repeat propagation. The current investigation refines this stage by additional thermodynamic considerations and elucidates the fundamental mechanism underlying propagation. Four different HD types were designed to extend the range of melting temperatures and to simultaneously modify the stabilities of their secondary structures. Following the propagation kinetics with these, using real-time PCR at different temperatures revealed a new stage in the MPR, amplification of an ID by an original HD, and enabled us to decipher the biphasic kinetics of the process. This amplification merges with the propagation stage if the lifetime of the staggered conformation of the ID is sufficiently long for DNA polymerase to fill in the overhangs. The observed increase with temperature of thermodynamically unfavorable conformations of singlet and doublet HDs that underlies, respectively, MPR initiation and propagation is well correlated with simulations by UNAFold.     

Simulation of tunneling in enzyme catalysis by combining a biased propagation approach and the quantum classical path method: application to lipoxygenase

The ability of using wave function propagation approaches to simulate isotope effects in enzymes is explored, focusing on the large H/D kinetic isotope effect of soybean lipoxygenase-1 (SLO-1). The H/D kinetic isotope effect (KIE) is calculated as the ratio of the rate constants for hydrogen and deuterium transfer. The rate constants are calculated from the time course of the H and D nuclear wave functions. The propagations are done using one-dimensional proton potentials generated as sections from the full multidimensional surface of the reacting system in the protein. The sections are obtained during a classical empirical valence bond (EVB) molecular dynamics simulation of SLO-1. Since the propagations require an extremely long time for treating realistic activation barriers, it is essential to use an effective biasing approach. Thus, we develop here an approach that uses the classical quantum path (QCP) method to evaluate the quantum free energy change associated with the biasing potential. This approach provides an interesting alternative to full QCP simulations and to other current approaches for simulating isotope effects in proteins. In particular, this approach can be used to evaluate the quantum mechanical transmission factor or other dynamical effects, while still obtaining reliable quantized activation free energies due to the QCP correction.     

Pair correlation functions in mixtures of Lennard-Jones particles

The pair correlation functions for a mixture of two Lennard-Jones particles were computed by both the Percus-Yevick equations and by molecular dynamics. The changes in the pair correlation function resulting from changes in the composition of the mixtures are quite unexpected. Essentially, identical changes are obtained from the Percus-Yevick equations and from molecular dynamics simulations. The molecular reason for this unexpected behavior is discussed.     

On zero-sum partitions and anti-magic trees

We study zero-sum partitions of subsets in abelian groups, and apply the results to the study of anti-magic trees. Extension to the nonabelian case is also given.     

Solvent-induced forces in protein folding reflections on the protein folding problem

It is shown that the solvent induced forces on hydrophilic groups are the strongest ones. The relevance of this finding to protein folding is discussed.     

Water’s contribution in providing strong solvent-induced forces in protein folding

It is commonly accepted that water plays an essential role in determining both the stability of the 3D structure of protein, as well as speed of the protein folding process. How exactly water does that, is still very controversial. Until recently it was believed that various hydrophobic effects, which originate from the solvent, are the dominant factors. In the first part of this article we discuss the paradigm shift from hydrophobic (H?O), to a hydrophilic (H?I) based theory of protein folding. Next, we analyze the types of solvent-induced forces that are exerted on various groups on the protein. We find that the H?I–H?I solvent-induced forces are likely to be the strongest. These forces originate from water molecules forming hydrogen-bonded-bridges between two, or more hydrophilic groups attached to the protein. Therefore, it is argued that these forces are also the forces that force the protein to fold, in a short time, along a narrow range of pathways. This paradigm shift brings us, as close as we can hope for, to a solution to the general problem of protein folding.     

Multiscale modeling of biological functions

Recent years have witnessed a tremendous explosion in computational power, which in turn has resulted in great progress in the complexity of the biological and chemical problems that can be addressed by means of all-atom simulations. Despite this, however, our computational time is not infinite, and in fact many of the key problems of the field were resolved long before the existence of the current levels of computational power. This review will start by presenting a brief historical overview of the use of multiscale simulations in biology, and then present some key developments in the field, highlighting several cases where the use of a physically sound simplification is clearly superior to a brute-force approach. Finally, some potential future directions will be discussed.     

An Analytical Solution for Unsteady Flow in a Phreatic Aquifer in the Case of Continuous Rise

In this study, we examine the classical problem of unsteady flow in a phreatic aquifer, induced by continuous rise of the water flux and head on its boundary. A closed-form analytical solution for the governing Boussinesq equation is derived for a semi-infinite aquifer.     

Some aspects of the protein folding problem examined in one-dimensional systems

Some concepts, such as energy landscape, Gibbs energy landscape, and cooperativity, frequently used in the theory of protein folding, are examined exactly in one-dimensional systems. It is shown that much of the confusion that exists regarding these, and other concepts arise from the misinterpretation of Anfinsen's thermodynamic hypothesis.