6 research outputs found
High-throughput Binding Affinity Calculations at Extreme Scales
Resistance to chemotherapy and molecularly targeted therapies is a major
factor in limiting the effectiveness of cancer treatment. In many cases,
resistance can be linked to genetic changes in target proteins, either
pre-existing or evolutionarily selected during treatment. Key to overcoming
this challenge is an understanding of the molecular determinants of drug
binding. Using multi-stage pipelines of molecular simulations we can gain
insights into the binding free energy and the residence time of a ligand, which
can inform both stratified and personal treatment regimes and drug development.
To support the scalable, adaptive and automated calculation of the binding free
energy on high-performance computing resources, we introduce the High-
throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block
approach in order to attain both workflow flexibility and performance. We
demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage
binding affinity calculation pipelines. This permits a rapid time-to-solution
that is essentially invariant of the calculation protocol, size of candidate
ligands and number of ensemble simulations. As such, HTBAC advances the state
of the art of binding affinity calculations and protocols
Concurrent and Adaptive Extreme Scale Binding Free Energy Calculations
The efficacy of drug treatments depends on how tightly small molecules bind
to their target proteins. The rapid and accurate quantification of the strength
of these interactions (as measured by binding affinity) is a grand challenge of
computational chemistry, surmounting which could revolutionize drug design and
provide the platform for patient-specific medicine. Recent evidence suggests
that molecular dynamics (MD) can achieve useful predictive accuracy (< 1
kcal/mol). For this predictive accuracy to impact clinical decision making,
binding free energy computational campaigns must provide results rapidly and
without loss of accuracy. This demands advances in algorithms, scalable
software systems, and efficient utilization of supercomputing resources. We
introduce a framework called HTBAC, designed to support accurate and scalable
drug binding affinity calculations, while marshaling large simulation
campaigns. We show that HTBAC supports the specification and execution of
free-energy protocols at scale. This paper makes three main contributions: (1)
shows the importance of adaptive execution for ensemble-based free energy
protocols to improve binding affinity accuracy; (2) presents and characterizes
HTBAC -- a software system that enables the scalable and adaptive execution of
binding affinity protocols at scale; and (3) for a widely used free-energy
protocol (TIES), shows improvements in the accuracy of simulations for a fixed
amount of resource, or reduced resource consumption for a fixed accuracy as a
consequence of adaptive execution
Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression
A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren\u27s likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren\u27s retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression