What is the Optimal Dipole Moment for Nonpolarizable Models of Liquids?

In classical nonpolarizable models, electrostatic interactions are usually described by assigning fixed partial charges to interaction sites. Despite the multitude of methods and theories proposed over the years for partial charge assignment, a fundamental question remains─what is the correct degree of polarization that a fixed-charge model should possess to provide the best balance of interactions (including induction effects) and yield the best description of the potential energy surface of a liquid phase? We address this question by approaching it from two separate and independent viewpoints: the QUantum mechanical BEspoke (QUBE) approach, which assigns bespoke force field parameters for individual molecules from calculations with minimal empirical fitting, and the Polarization-Consistent Approach (PolCA) force field, based on empirical fitting of force field parameters with an emphasis on transferability by rigorously accounting for polarization effects in the parameterization process. We show that the two approaches yield consistent answers to the above question, namely, that the dipole moment of the model should be approximately halfway between those of the gas and the liquid phase.

Exploration and validation of force field design protocols through QM-to-MM mapping.

The scale of the parameter optimisation problem in traditional molecular mechanics force field construction means that design of a new force field is a long process, and sub-optimal choices made in the early stages can persist for many generations. We hypothesise that careful use of quantum mechanics to inform molecular mechanics parameter derivation (QM-to-MM mapping) should be used to significantly reduce the number of parameters that require fitting to experiment and increase the pace of force field development. Here, we design and train a collection of 15 new protocols for small, organic molecule force field derivation, and test their accuracy against experimental liquid properties.

Implementation of the QUBE Force Field in SOMD for High-Throughput Alchemical Free-Energy Calculations.

The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein-ligand binding. To date, the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD.

The role of CACNA1S in predisposition to malignant hyperthermia.

Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the alpha1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK.

Genetic variation in RYR1 and malignant hyperthermia phenotypes.

Background: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype.

Methods: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH.