This document provides an introduction to centrosomal variants and prioritizes cancer-causing mutations in centromere protein families using an SVM approach. It discusses centromeres, their role in cell division, and diseases linked to centromere dysfunction. It then describes machine learning methods like SVMs and applies an SVM classifier to identify cancer-associated variants in centromere proteins using training data from databases. Molecular dynamics simulations analyze structural effects of mutations on centromere protein E (CENPE) and its interaction with ATP. Tools like SIFT and Polyphen were used to collect training data, an SVM model was generated using RBF kernels and cross-validation, and references are provided.
PICS: Pathway Informed Classification System for cancer analysis using gene e...David Craft
We introduce PICS (Pathway Informed Classification System) for classifying cancers based on tumor sample gene expression levels. The method clearly separates a pan-cancer dataset into their tissue of origin and is also able to sub-classify individual cancer datasets into distinct survival classes. Gene expression values are collapsed into pathway scores that reveal which biological activities are most useful for clustering cancer cohorts into sub-types. Variants of the method allow it to be used on datasets that do and do not contain non-cancerous samples. Activity levels of all types of pathways, broadly grouped into metabolic, cellular processes and signaling, and immune system, are useful for separating the pan-cancer cohort. In the clustering of specific cancer types, certain pathway types become more valuable depending on the site being studied. For lung cancer, signaling pathways dominate, for pancreatic cancer signaling and metabolic pathways, and for melanoma immune system pathways are the most useful. This work suggests the utility of pathway level genomic analysis and points in the direction of using pathway classification for predicting the efficacy and side effects of drugs and radiation.
Presentation by Scott Woodman, MD, PhD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative.
PICS: Pathway Informed Classification System for cancer analysis using gene e...David Craft
We introduce PICS (Pathway Informed Classification System) for classifying cancers based on tumor sample gene expression levels. The method clearly separates a pan-cancer dataset into their tissue of origin and is also able to sub-classify individual cancer datasets into distinct survival classes. Gene expression values are collapsed into pathway scores that reveal which biological activities are most useful for clustering cancer cohorts into sub-types. Variants of the method allow it to be used on datasets that do and do not contain non-cancerous samples. Activity levels of all types of pathways, broadly grouped into metabolic, cellular processes and signaling, and immune system, are useful for separating the pan-cancer cohort. In the clustering of specific cancer types, certain pathway types become more valuable depending on the site being studied. For lung cancer, signaling pathways dominate, for pancreatic cancer signaling and metabolic pathways, and for melanoma immune system pathways are the most useful. This work suggests the utility of pathway level genomic analysis and points in the direction of using pathway classification for predicting the efficacy and side effects of drugs and radiation.
Presentation by Scott Woodman, MD, PhD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative.
Molecular imaging has revolutionized our perceptions of imaging. This high impact field is finding transformative applications in the understanding, detection, and treatment of nearly all diseases.
The field of molecular imaging is a an exciting fusion and integration of many different disciplines including molecular biology, chemistry and probe design, imaging technologies, visualization, and image analysis, that are focused on understanding, detecting, and treating oncological, neurological, cardiovascular, inflammatory, metabolic, and infectious diseases. Based on their strengths, different imaging modalities provide different but equally valuable information that can be integrated in advancing our understanding of these diseases.
As the era of ‘omics’ progresses towards personalized medicine, the field of molecular imaging is finding multiple uses in noninvasive characterization of the molecular features of diseases and their impact on function. In complex diseases such as cancer, with its tremendous genetic diversity, it is becoming increasingly important to develop molecularly-targeted treatment strategies that combine detection with treatment.
HDAC4 and HDAC7 Promote Breast and Ovarian Cancer Cell Migration by Regulatin...CrimsonpublishersCancer
Breast and ovarian cancer have been remained as a highly malignant tumor among women, posing a serious threat to women health worldwide. In this study, we were aimed to investigate the underlying mechanism of breast and ovarian cancer cell migration. Wound healing assay showed that MDA-MB-231and C13* have higher migration potential compare with MCF-7 and OV2078 cells, as well as regulated epithelial-mesenchymal transition (EMT) marker. We found that HDAC4 and HADC7 mRNA are up regulated in MDA-MB-231 and C13* cells. Moreover, target HDAC4 and HDAC7 by TSA or shRNA block MDA-MB-231and C13* migration. These results reveal a new link between HDACs and EMT in the regulation of breast and ovarian cancer migration.
A high-throughput approach for multi-omic testing for prostate cancer researchThermo Fisher Scientific
The proliferation of genetic testing technologies and genome-scale studies has increased our understanding of the genetic basis of complex diseases. However, this information alone tells an incomplete story of the underlying biology. Integrative approaches that combine data from multiple sources, such as the genome, transcriptome and/or proteome, can provide a more comprehensive and multi-dimensional model of complex diseases. Similarly, the integration of multiple data types in disease screening can improve our understanding of disease in populations. In a series of groundbreaking multi-omic, population-based studies of prostate cancer, researchers at the Karolinska Institutet in Stockholm, Sweden identified sets of genetic and protein biomarkers that when evaluated together with other clinical research data performed significantly better in predicting cancer risk (1,2) than the most-widely used single protein biomarker, the prostate-specific antigen (PSA).
Identifying novel and druggable targets in a triple negative breast cancer ce...Thermo Fisher Scientific
In this study, we developed a CRISPR/Cas9-based high throughput loss-of-function screen for identifying target genes responsible for the tumor proliferation and growth in TNBC. Our initial focus was to identify essential kinases in MDA-MB-231 cell line using the Invitrogen™ LentiArray™ Human Kinase CRISPR Library, which targets 840 kinases with up to 4 different gRNAs per protein kinase for complete gene knockout. This functional screen identified over 90 protein kinases that are essential for cell viability and cell proliferation. Ten of these hits (CDK1, CDK2, CDK8, CDK10, CDK11A, CDK19, CDK19, CDC7, EPHA2 and WEE1) are well-known targets validated in the literature. Currently, we are in the process validating the novel hits through target gene sequencing, western blotting and target specific small molecule kinase inhibitors.
Molecular imaging has revolutionized our perceptions of imaging. This high impact field is finding transformative applications in the understanding, detection, and treatment of nearly all diseases.
The field of molecular imaging is a an exciting fusion and integration of many different disciplines including molecular biology, chemistry and probe design, imaging technologies, visualization, and image analysis, that are focused on understanding, detecting, and treating oncological, neurological, cardiovascular, inflammatory, metabolic, and infectious diseases. Based on their strengths, different imaging modalities provide different but equally valuable information that can be integrated in advancing our understanding of these diseases.
As the era of ‘omics’ progresses towards personalized medicine, the field of molecular imaging is finding multiple uses in noninvasive characterization of the molecular features of diseases and their impact on function. In complex diseases such as cancer, with its tremendous genetic diversity, it is becoming increasingly important to develop molecularly-targeted treatment strategies that combine detection with treatment.
HDAC4 and HDAC7 Promote Breast and Ovarian Cancer Cell Migration by Regulatin...CrimsonpublishersCancer
Breast and ovarian cancer have been remained as a highly malignant tumor among women, posing a serious threat to women health worldwide. In this study, we were aimed to investigate the underlying mechanism of breast and ovarian cancer cell migration. Wound healing assay showed that MDA-MB-231and C13* have higher migration potential compare with MCF-7 and OV2078 cells, as well as regulated epithelial-mesenchymal transition (EMT) marker. We found that HDAC4 and HADC7 mRNA are up regulated in MDA-MB-231 and C13* cells. Moreover, target HDAC4 and HDAC7 by TSA or shRNA block MDA-MB-231and C13* migration. These results reveal a new link between HDACs and EMT in the regulation of breast and ovarian cancer migration.
A high-throughput approach for multi-omic testing for prostate cancer researchThermo Fisher Scientific
The proliferation of genetic testing technologies and genome-scale studies has increased our understanding of the genetic basis of complex diseases. However, this information alone tells an incomplete story of the underlying biology. Integrative approaches that combine data from multiple sources, such as the genome, transcriptome and/or proteome, can provide a more comprehensive and multi-dimensional model of complex diseases. Similarly, the integration of multiple data types in disease screening can improve our understanding of disease in populations. In a series of groundbreaking multi-omic, population-based studies of prostate cancer, researchers at the Karolinska Institutet in Stockholm, Sweden identified sets of genetic and protein biomarkers that when evaluated together with other clinical research data performed significantly better in predicting cancer risk (1,2) than the most-widely used single protein biomarker, the prostate-specific antigen (PSA).
Identifying novel and druggable targets in a triple negative breast cancer ce...Thermo Fisher Scientific
In this study, we developed a CRISPR/Cas9-based high throughput loss-of-function screen for identifying target genes responsible for the tumor proliferation and growth in TNBC. Our initial focus was to identify essential kinases in MDA-MB-231 cell line using the Invitrogen™ LentiArray™ Human Kinase CRISPR Library, which targets 840 kinases with up to 4 different gRNAs per protein kinase for complete gene knockout. This functional screen identified over 90 protein kinases that are essential for cell viability and cell proliferation. Ten of these hits (CDK1, CDK2, CDK8, CDK10, CDK11A, CDK19, CDK19, CDC7, EPHA2 and WEE1) are well-known targets validated in the literature. Currently, we are in the process validating the novel hits through target gene sequencing, western blotting and target specific small molecule kinase inhibitors.
Developing a framework for for detection of low frequency somatic genetic alt...Ronak Shah
Cancer is a complex, heterogeneous disease of the genome. Most cancers result
from an accumulation of multiple genetic alterations that lead to dysfunction of cancer-associated
genes and pathways. Recent advances in sequencing technology have enabled comprehensive
profiling of genetic alterations in cancer. We have established a targeted sequencing platform
(IMPACT: Integrated Mutation Profiling of Actionable Cancer Targets) using hybridization capture and
next-generation sequencing (NGS) technology, which can reveal mutations, indels and copy number
alterations involving 340 cancer related genes.
Now a day’s, pharma research is facing challenges in
deciphering molecular understanding of disease initiation,
progress and establishment as well as performance
assessment of drug molecule on such phases of disease
development. Emerging of next generation sequencing
bases molecular tools were found to be a key method for
creating genome wide genomics landscape of gene
mutations, gene expression and gene regulation events.
Although NGS is a powerful tool for molecular research but
same time it have its own technical challenges. Few major
challenges of NGS based pharmacogenomics is
summarized below
Forecasting clinical behavior and therapeutic response of human cancer currently utilizes a limited number of tumor markers in combination with characteristics of the patient and their disease. Although few tumor markers and molecular targets exist for evaluation, the wealth of information derived from recent sequencing advancements provides greater opportunities to develop more precise tests for diagnostics, prognostics, therapy selection and monitoring in the future. The objectives of this study are to study miRNA and mRNA expression profiles of laser capture microdissection (LCM)-procured tumor cells and intact serial sections of breast tissue samples using next generation sequencing (NGS) methods. Our hypothesis is that miRNA signatures discerned from specific tumor cell populations more precisely correlate with behavior than that provided by conventional biomarkers from intact tissue samples. Additionally, we hypothesize the data generated in this study will present mRNA signatures informative for breast tumor research and support our miRNA findings through suggesting relevant miRNA:mRNA target associations.
De-identified frozen research samples of primary invasive ductal tumors of known grade and biomarker status containing 35-70% tumor were selected from an IRB-approved Biorepository. Comparison of expressed miRNAs from intact tissue sections with those of cognate tumor cells procured by LCM revealed, in general, that smaller defined miRNA gene sets were expressed in LCM isolated populations of tumor cells. In addition to miRNA sequencing, targeted RNA sequencing with the Ion AmpliSeq™ Transcriptome Human Gene Expression Kit was used to capture mRNA expression information. Data presented here demonstrates high mapping rates for targeted mRNA (>91% of reads) and miRNA (> 88% of reads) libraries. We also demonstrate high technical reproducibility between multiple libraries from the same tumor sample for both mRNA (R>0.99) and miRNA (R>0.97) libraries. We also report suggested miRNA:mRNA target associations identified in our set of breast tumor research samples. These data provide insights into breast cancer biology that may lead to new molecular diagnostics and targets for drug design in the future as well as an improved understanding of the molecular basis of clinical behavior and potential therapeutic response.
Advanced Genome Engineering Services and Transgenic Model Generation
at MSU’s Transgenic and Genome Editing Facility
Huirong Xie, Elena Demireva, Nate Kauffman, Richard Neubig
Analytical performance of a novel next generation sequencing assay for Myeloi...Thermo Fisher Scientific
To support clinical and translational research into precision oncology strategies for myeloid cancers, a next-generation sequencing (NGS) assay was developed to detect common and relevant somatic alterations. To define gene targets that were recurrently altered in myeloid cancers and relevant for clinical and translational research, an extensive survey of investigators at hematology oncology research labs was performed.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Unveiling the Energy Potential of Marshmallow Deposits.pdf
SVM based prioritization of cancer causing mutations in centromere protein family
1. A short introduction to Centrosomal
Variants
SVM based prioritization of cancer causing
mutations in centromere protein family
2. Centromere
The centromere is the part of a chromosome that links sister
chromatids.
During anaphase of mitosis, paired centromeres in each distinct
chromosome begin to move apart as daughter chromosomes
migrate centromere first toward opposite ends of the cell.
It is the most condensed and constricted region of a chromosome.
It serves as the point of attachment for spindle fibers.
Deregulation in the their activity leads to several checkpoint
dissorders and pathogeneticities.
4. Few important Centromere protein
families
CEP family proteins
CENP family proteins
MAD family proteins
hSAS family proteins
CEPTIN family proteins
6. Proteins selected for evaluation
CENPA, CENPB, CENPC, CENPE, CENPF, CENPH, CENPI, CENPJ, CENPK, CENPL,
CENPM, CENPN, CENPO, CENPP, CENPQ, CENPR, CENPS, CENPT, CENPU, CENPV,
CENPW, CENPX, CENPY, CENPZ
Total 823 structural variants from CENP protein family were collected for
this study
7. Machine Learning: What is it all about
1. Computers are very intelligent and has greater compilaton ability.
2. It can learn everything, no matter what you give.
3. Training data must not contain any wrong values.
4. To prevent the use of spurious datas we must validate and scale the entire dataset
before starting the training session.
5. There are three different methodologies in machine learning.
a. Supervised learning methods
b. Unsupervised learning methods
c. Reinforcement learning methods
8. Supervised learning is the machine learning task of inferring a function from
supervised (labeled) training data.
A supervised learning algorithm analyzes the training data and produces an inferred
function.
The parallel task in human and animal psychology is often carride out by this method.
Few widely used supervised learning algorithms are:
1. Support vector machines
2. Bayesian statistics
3. Artificial neural network
4. Random Forests
5. Regression analysis
9. Support Vector Machines
A support vector machine (SVM) is a concept in statistics and computer science for a set of
related supervised learning methods that analyze data and recognize patterns, used for
classification and regression analysis.
Given a set of training examples, each marked as belonging to one of two categories, an
SVM training algorithm builds a model that assigns new examples into one category or
the other.
More formally, a support vector machine constructs a hyperplane or set of hyperplanes in a
high or infinite dimensional space, which can be used for classification.
Here consider Đ as a training data for which,
Đ = {(xi,yi) | xi Є Rp, yi Є {1, -1}} (for i=1 to n)
For training we used radial basis function kernal for greater accuarcy
(RBF): K(xi , xj) = exp(−γ ||xi − xj||^2), γ > 0.
11. 1. Examination of protocol
2. Application of protocol to collect datasets for training the machine
4. Application of designed classifier to identify the cancer associated
mutations in CENP family proteins.
3. Designing a Support Vector Machine classifier system using machine
learning algorithm
Methodology
5. Studying the dynamic behaviour of cancer associated structural variants
12. Examination of protocol was carried out on CENPE proteinExamination of protocol was carried out on CENPE protein
➔Centromere-associated protein-E (CENPE), a protein with 2701 amino acids and relative
molecular weight of 312 kDa, is highly expressed in mitosis and accumulates in the cell just
prior to mitosis.
➔It is required for efficient, stable microtubule capture at kinetochores.
➔It plays an essential role in integrating the mechanics of microtubule-chromosome
interactions with mitotic checkpoint signaling, and has emerged as a novel target for cancer
therapy.
➔It contains ATP-sensitive motor-like domain at its N-terminus that is actively involved in
hydrolyzing ATP to produce directed mechanical force along microtubules.
➔Absence of CENPE reduces tension at the bi-orientated chromosomes resulting in
misaligned chromosomes in the metaphase plate, leading to metaphase arrest.
➔CENPE expression was also found to be reduced in human HCC tissue, and lower
expression of CENPE was found to be inducing aneuploidy in LO2 cells.
13. Prediction of oncogenic mutant in CENPE using SNP prediction tools
We first collected 100 nsSNP reported in CENPE coding gene from NCBI dbSNP database.
SIFT, Polyphen, PhDSnp, Pmut, CancPredict and Dr. Cancer tools were used to identify the
cancer associated SNP from the available dataset.
We found Y63H as highly deleterious and cancer associated using above tools.
To analyse the structural consequences of this mutation we further carried out olecular
dynamic simulation of CENPE native and mutant motor domain for 5 ns timescale.
Insilico X-ray scatering was carried out throughout the simulation in order to observe the
change in ionic density in native and mutant structure.
Root mean square deviation was then plotted to analyze the relative fluctuation of the
structures.
18. Time (seconds) Time (seconds)
Native Mutant
CENPE-ATP
CENPE-ADP CENPE-ADP
CENPE-ATP
Time (seconds) Time (seconds)
19. Tools used to collect training data's
Row 1 Row 2 Row 3 Row 4
0
2
4
6
8
10
12
Column 1
Column 2
Column 3
Tools used to collect SNP training datas
1. SIFT, Polyphen, PhDSnp, Pmut, CancPredict and Dr. Cancer tools were used to collect the SNP
datasets.
2. Cancer variant datas were obtained from Swissvar database.
3. Neutral variants were randomly picked from Swissprot database.
4. Scaling, training and model generation were carried out using support vector machine algorithm.
5. RBF kernal was used to generate the classifier model.
6. Rescaling and cross-validation was carried out by changing the Ć and γ values untill the maximum
accuracy was obtained.
20.
21. Model designed for neutral variants
Model designed for 100 Neutral and Cancer variants
22. References
Kim Y, Holland AJ, Lan W, Cleveland DW. Aurora kinases and protein phosphatase 1
mediate chromosome congression through regulation of CENP-E. Cell. 2010 142:444-
55.
Maia AF, Feijão T, Vromans MJ, Sunkel CE, Lens SM. Aurora B kinase cooperates with
CENP-E to promote timely anaphase onset. Chromosoma. 2010 119:405-13.
Yang CP, Liu L, Ikui AE, Horwitz SB. The interaction between mitotic checkpoint proteins,
CENP-E and BubR1, is diminished in epothilone B-resistant A549 cells. Cell Cycle.
2010 Mar 15;9(6):1207-13.
Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: Algorithms for
Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J Chem Theory
Comput. 4:435–447.
Frisch C, Fersht AR, Schreiber G. Experimental assignment of the structure of the transition
state for the association of barnase and barstar. J Mol Biol. 2001 308:69-77.