Description

Nucleic acids are an important class of biological macromolecules that carry out a variety of cellular roles. For many functions, naturally occurring DNA and RNA molecules need to fold into precise three-dimensional structures. Due to their self-assembling characteristics, nucleic acids have also been widely studied in the field of nanotechnology, and a diverse range of intricate three-dimensional nanostructures have been designed and synthesized. Different physical terms such as base-pairing and stacking interactions, tertiary contacts, electrostatic interactions and entropy all affect nucleic acid folding and structure. Here we review general computational approaches developed to model nucleic acid systems. We focus on four key areas of nucleic acid modeling: molecular representation, potential energy function, degrees of freedom and sampling algorithm.

Molecular Modeling

Recent discoveries of RNA's various gene regulation roles and the potential applications of nucleic acid nanostructures to biocomputing and nanotechnology there has been extensive research into developing computational tools for modeling and manipulating nucleic acid structure. Since computational modeling can be used to address a wide range of problems that vary in complexity and resolution, an appropriate choice of algorithm or modeling platform is required. We discuss four main aspects of nucleic acid modeling here. Firstly, molecular representation; secondly, potential energy function; thirdly, degrees of freedom; and fourthly, sampling algorithm. We focus on general modeling techniques and strategies that are applicable to an array of modeling purposes such as generating an ensemble of plausible molecular models, identifying a native like molecular structure, studying folding kinetics, probing the effects of base mutations, refining molecular models and modeling with limited experimental data.

In molecular modeling, a potential energy function is required to distinguish physical and biologically relevant conformations. These potentials come in varying degrees of precision and complexity ranging from a primitive function considering only steric restraints to one that depends on quantum mechanical calculations. The choice of potential is critical to the efficacy of molecular modeling. The accuracy of modeling depends on the correctness of the potential whereas sampling. Another approach to coarse-graining large systems is to use alternate sets of DOFs while retaining an all-atom representation. By modeling using dihedral or torsional DOFs instead of all-atom Cartesian DOFs, dimensionality number of DOFs is substantially reduced.

Mipomersen

Mipomersen is an ASO that acts as an inhibitor of apolipoprotein B-100 synthesis, which is an essential component of both Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL). It has been approved for patients diagnosed with homozygous familial Hypercholesterolemia (HoFH). Familial hypercholesterolemia is an autosomal dominant genetic disorder resulting from mutations of the Low Density Lipoprotein Cholesterol (LDL-C) receptor, apolipoprotein B, or pro-protein convertase subtilisin or kexin. The standard of care before approval of mipomersen for patients with HoFH was weekly or bi-weekly LDL apheresis. Mipomersen binds to the mRNA of the abnormal apo B in patients with HoFH and inhibits the synthesis of mutated apo B protein so that LDL-C is phagocytosed in the hepatocytes and cleared from the blood stream. Mipomersen is long acting with an elimination half-life ranging between 21 and 33 days depending on the administered dose, and attributed largely to the fact that most of the compound is bound to plasma proteins. Hence, mipomersen is administered once a week as subcutaneous injection. At 26 weeks a mean reduction of LDL was observed between 25 and 36 compared with placebo. The most commonly observed adverse drug reactions include local injection site reactions such as pruritis, erythema and pain and systemic reactions such as fatigue, pyrexia, chills, malaise, myalgia and arthralgia. As liver enzymes were found to be elevated with the drug administration, mipomersen is contraindicated in patients with moderate or severe hepatic impairment. The fundamental basis of using nucleic acids except for gene therapy in therapeutics is either inhibition of DNA or RNA expression, thereby halting production of abnormal protein related to a disease while leaving all other proteins unaffected. Therapeutic Nucleic Acids (TNAs) are nucleic acids themselves or closely related compounds used to treat disease. Although various types of TNAs exist, they share a common mechanism of action that is mediated by sequence-specific recognition of endogenous nucleic acids through Watson–Crick base pairing. Their drug development has specific requirements that are unique as they fall somewhere between small molecules and biologics. TNA are charged, high molecular weight compounds with physicochemical properties different from small molecule drugs, and are unstable in a biological environment. In addition, TNA have to be delivered to the correct intracellular compartment. Because they are chemically synthesized, regulators considered that they are New Chemical Entities (NCEs). However, the above mentioned characteristics make them closer to New Biological Entities (NBEs).