Next Article in Journal
A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia
Next Article in Special Issue
Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia
Previous Article in Journal
Effect of Trichoderma velutinum and Rhizoctonia solani on the Metabolome of Bean Plants (Phaseolus vulgaris L.)
Previous Article in Special Issue
Methylation-Based Classification of Cervical Squamous Cell Carcinoma into Two New Subclasses Differing in Immune-Related Gene Expression
Open AccessReview

Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases

Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 548; https://doi.org/10.3390/ijms20030548
Received: 22 December 2018 / Revised: 25 January 2019 / Accepted: 26 January 2019 / Published: 28 January 2019
Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context in which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico–chemical properties of the amino acids (native vs. mutant) can still have minimal effects on protein thermodynamics. However, if a mutation causes significant perturbation by either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize the effects of mutations on two important biophysical properties, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical properties. View Full-Text
Keywords: mutations; disease-causing mutations; polymorphism; folding free energy change; binding free energy change; drug discovery; in silico screening mutations; disease-causing mutations; polymorphism; folding free energy change; binding free energy change; drug discovery; in silico screening
Show Figures

Graphical abstract

MDPI and ACS Style

Peng, Y.; Alexov, E.; Basu, S. Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases. Int. J. Mol. Sci. 2019, 20, 548.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop