An in silico study of the molecular basis of B-RAF activation and conformational stability

<p>Abstract</p> <p>Background</p> <p>B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood.</p> <p>Results</p> <p>In this study we suggest a novel molecular basis of B-RAF activation based on molecular dynamics (MD) simulations of B-RAF^WTand the B-RAF^V600E, B-RAF^K601Eand B-RAF^D594Vmutants. A strong hydrogen bond network was identified in B-RAF^WTin which the interactions between Lys601 and the well known catalytic residues Lys483, Glu501 and Asp594 play an important role. It was found that several mutations, which directly or indirectly destabilized the interactions between these residues within this network, contributed to the changes in B-RAF activity.</p> <p>Conclusion</p> <p>Our results showed that the above mechanisms lead to the disruption of the electrostatic interactions between the A-loop and the αC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAF^D594Vmutant that has impaired kinase activity, and in B-RAF^WTthese interactions were strong and stabilized the kinase inactive form.</p

A Theoretical Information Approach to Ring and Total Aromaticity in Ground and Excited States

Applying the Shannon equation to the density matrix of a molecule, an information index is specified for the quantitative estimation of the ring and total aromaticity of molecules in ground · and excited states. The approach is applicable within each LCAO- method. The information index reproduces well the classification of molecules as aromatic, nonaromatic, and antiaromatic. It also correlates with results of other authors obtained by radically different approaches. A tendency is found for the aromaticity of aromatic molecules to decrease and of antiaromatic molecules to increase when the molecule is excited to the S1-state

Acetylene, Vinylidene, and the Vinyl Cation in Ground and Excited States

Ab initio calculations using the improved virtual orbital formalism are reported for acetylene, vinylidene, and the vinyl cation, C2H,+, in classical and bridged geometries. Electronic transition energies and equilibrium geometries for ground and lower lying electronically excited states have been calculated. A modified Walsh diagram for acetylene and simple molecular orbital considerations explain excited state structures and energy orderings. While acetylene in the ground state is much more stable than vinylidene, the energies of several corresponding excited states are comparable. The stabilities of bridged and classical structures of the vinyl cation are very similar in the ground state, but in the various excited states either strcture can predominate. The proton affinity of acetylene in the ground state should be appreciably lower than in excited states

Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy

Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower's sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a template defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown-models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity

A Computational Assay of Estrogen Receptor alpha Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers

Somatic mutations of the Estrogen Receptor alpha (ER alpha) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 mu s) molecular dynamics simulations revealed that recurrent ER alpha. polymorphisms (i.e. L536Q, Y5375, Y537N, D538G) (mER alpha) are constitutively active in their apo form and that they prompt the selection of an agonist (active)-like conformation even upon antagonists binding. Interestingly, our simulations rationalize, for thefirst time, the efficacy profile of (pre)clinically used Selective Estrogen Receptor Modulators/Downregulators (SERMs/SERDs) against these variants, enlightening, at atomistic level of detail, the key common structural traits needed by drugs able to effectively fight refractory BC types. This knowledge represents a key advancement for mechanism-based therapeutics targeting resistant ER alpha isoforms, potentially allowing the community to move a step closer to 'precision medicine' calibrated on patients' genetic profiles and disease progression