Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations.

The initial phases of drug discovery - in silico drug design - could benefit from first principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines - so far an unmet and crucial goal - will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance. We also demonstrate for the first time strong scaling of MiMiC-QM/MM MD simulations with parallel efficiency of ∼70% up to >80,000 cores. Thus, among many others, the MiMiC interface represents a promising candidate toward exascale applications by combining machine learning with statistical mechanics based algorithms tailored for exascale supercomputers.

Structure and dynamics of an archetypal DNA nanoarchitecture revealed via cryo-EM and molecular dynamics simulations.

DNA can be folded into rationally designed, unique, and functional materials. To fully realise the potential of these DNA materials, a fundamental understanding of their structure and dynamics is necessary, both in simple solvents as well as more complex and diverse anisotropic environments. Here we analyse an archetypal six-duplex DNA nanoarchitecture with single-particle cryo-electron microscopy and molecular dynamics simulations in solvents of tunable ionic strength and within the anisotropic environment of biological membranes. Outside lipid bilayers, the six-duplex bundle lacks the designed symmetrical barrel-type architecture. Rather, duplexes are arranged in non-hexagonal fashion and are disorted to form a wider, less elongated structure. Insertion into lipid membranes, however, restores the anticipated barrel shape due to lateral duplex compression by the bilayer. The salt concentration has a drastic impact on the stability of the inserted barrel-shaped DNA nanopore given the tunable electrostatic repulsion between the negatively charged duplexes. By synergistically combining experiments and simulations, we increase fundamental understanding into the environment-dependent structural dynamics of a widely used nanoarchitecture. This insight will pave the way for future engineering and biosensing applications.

Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective.

The dissociation rate (k off) associated with ligand unbinding events from proteins is a parameter of fundamental importance in drug design. Here we review recent major advancements in molecular simulation methodologies for the prediction of k off. Next, we discuss the impact of the potential energy function models on the accuracy of calculated k off values. Finally, we provide a perspective from high-performance computing and machine learning which might help improve such predictions.

Principles of Small-Molecule Transport through Synthetic Nanopores.

Synthetic nanopores made from DNA replicate the key biological processes of transporting molecular cargo across lipid bilayers. Understanding transport across the confined lumen of the nanopores is of fundamental interest and of relevance to their rational design for biotechnological applications. Here we reveal the transport principles of organic molecules through DNA nanopores by synergistically combining experiments and computer simulations. Using a highly parallel nanostructured platform, we synchronously measure the kinetic flux across hundreds of individual pores to obtain rate constants. The single-channel transport kinetics are close to the theoretical maximum, while selectivity is determined by the interplay of cargo charge and size, the pores' sterics and electrostatics, and the composition of the surrounding lipid bilayer. The narrow distribution of transport rates implies a high structural homogeneity of DNA nanopores. The molecular passageway through the nanopore is elucidated via coarse-grained constant-velocity steered molecular dynamics simulations. The ensemble simulations pinpoint with high resolution and statistical validity the selectivity filter within the channel lumen and determine the energetic factors governing transport. Our findings on these synthetic pores' structure-function relationship will serve to guide their rational engineering to tailor transport selectivity for cell biological research, sensing, and drug delivery.

Sequence-dependent structural properties of B-DNA: what have we learned in 40 years?

The structure of B-DNA, the physiological form of the DNA molecule, has been a central topic in biology, chemistry and physics. Far from uniform and rigid, the double helix was revealed as a flexible and structurally polymorphic molecule. Conformational changes that lead to local and global changes in the helix geometry are mediated by a complex choreography of base and backbone rearrangements affecting the ability of the B-DNA to recognize ligands and consequently on its functionality. In this sense, the knowledge obtained from the sequence-dependent structural properties of B-DNA has always been thought crucial to rationalize how ligands and, most notably, proteins recognize B-DNA and modulate its activity, i.e. the structural basis of gene regulation. Honouring the anniversary of the first high-resolution X-ray structure of a B-DNA molecule, in this contribution, we present the most important discoveries of the last 40 years on the sequence-dependent structural and dynamical properties of B-DNA, from the early beginnings to the current frontiers in the field.