Arthur M. Lesk
Encyclopedia
Arthur M. Lesk, is an accomplished protein science researcher, who is currently a professor of biochemistry
and molecular biology
at the Pennsylvania State University
, University Park.
, working at the MRC
Laboratory of Molecular Biology
in Cambridge
, United Kingdom
, discovered the relationship between changes in amino-acid sequence and changes in protein structure by analyzing the mechanism of evolution in protein families. This discovery has provided the quantitative basis for the most successful and widely used method of structure prediction, known as homology modelling.
Lesk and Chothia also studied the conformations of antigen-binding sites of immunoglobulins. They discovered the “canonical-structure model” for the conformation of the complementarity-determining regions of antibodies, and they applied this model to the analysis of antibody-germ-line genes, including the prediction of the structure of the corresponding proteins. This work has supported the “humanization” of antibodies for therapy in the treatment of cancer. “This approach to cancer therapy is based on the observation of H. Waldmann that rats can raise antibodies against human cancers, but that the rat antibodies lead to immune responses, similar to allergies, in human patients,” Lesk explains. “Humanization of these antibodies is the formation of hybrid molecules that are more human than rat, but that retain the therapeutic activity while reducing the patient’s immune response.”
Lesk’s work also involves the detailed comparison of proteins in different structural states as a means for understanding the mechanisms that enable the proteins to change conformation, both as part of their normal activity and in disease. The discovery and analysis of these mechanisms was the key to understanding conformation changes in serine protease inhibitors, also known as serpins, mutations of which are an important cause of several diseases, including emphysema and certain types of inherited mental illness.
Lesk used a systematic analysis of protein-folding patterns to develop a mathematical representation that aids in the recognition and classification of these patterns. He also wrote the first computer program to generate schematic diagrams of proteins using molecular graphics, and he developed many algorithms now used by other researchers to analyze the structures of proteins.
Lesk was formerly chair of the Task Group on Biological Macromolecules for the Committee on Data for Science and Technology (CODATA), which aimed to foster worldwide coordination of databases in molecular biology to enhance their quality and utility. He has given invited lectures and presentations related to his research at universities and professional conferences worldwide.
Lesk is a member of the American Physical Society
. He has published 189 scientific articles and 10 books related to his research
.
Prior to joining Penn State during the fall semester of 2003, Lesk was on the faculty of the clinical school at the University of Cambridge from 1990 to 2003. He was a group leader in the biocomputing program at the European Molecular Biology Laboratory in Heidelberg, Germany, from 1987 to 1990; a visiting scientist at MRC Laboratory of Molecular Biology in Cambridge, United Kingdom, between 1977 and 1990; and a professor of chemistry at Fairleigh Dickinson University in New Jersey from 1971 to 1987. He has held visiting fellowships at the University of Otago in New Zealand and Monash University in Australia. He also is a Life Member of Clare Hall at the University of Cambridge in the United Kingdom.
Along with Karl D. Hardman, Lesk wrote the first computer program
for generating the schematic diagram of protein structure
. It is known to produce one of the most effective representations of the protein structures and employs the classification scheme for Ribbon Diagrams created by Jane Richardson. Although these schematic diagrams are less detailed compared to the other representations, such as, picture stimulating wire models or space-filling models, it is more effective in presenting the topological relationships among elements of secondary structure
and protein
, due to its simplistic structural expression. This was then further improved by creating a program to produce stereoscopic pairs of diagrams. As a result, the viewer’s ability to perceive spatial relationship in complex molecules was enhanced.
Lesk received a bachelor’s degree, magna cum laude, from Harvard University in 1961. He received his doctoral degree from Princeton University in 1966. He also received a master’s degree from the University of Cambridge in the United Kingdom in 1999.
.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
and molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
at the Pennsylvania State University
Pennsylvania State University
The Pennsylvania State University, commonly referred to as Penn State or PSU, is a public research university with campuses and facilities throughout the state of Pennsylvania, United States. Founded in 1855, the university has a threefold mission of teaching, research, and public service...
, University Park.
Profile
Lesk has made significant contributions to the study of protein evolution. He and Cyrus ChothiaCyrus Chothia
Cyrus Chothia FRS is an emeritus scientist at the Medical Research Council Laboratory of Molecular Biology and emeritus fellow of Wolfson College, Cambridge....
, working at the MRC
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...
Laboratory of Molecular Biology
Laboratory of Molecular Biology
The Laboratory of Molecular Biology is a research institute in Cambridge, England, which was at the forefront of the revolution in molecular biology which occurred in the 1950–60s, since then it remains a major medical research laboratory with a much broader focus.-Early beginnings: 1947-61:Max...
in Cambridge
Cambridge
The city of Cambridge is a university town and the administrative centre of the county of Cambridgeshire, England. It lies in East Anglia about north of London. Cambridge is at the heart of the high-technology centre known as Silicon Fen – a play on Silicon Valley and the fens surrounding the...
, United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, discovered the relationship between changes in amino-acid sequence and changes in protein structure by analyzing the mechanism of evolution in protein families. This discovery has provided the quantitative basis for the most successful and widely used method of structure prediction, known as homology modelling.
Lesk and Chothia also studied the conformations of antigen-binding sites of immunoglobulins. They discovered the “canonical-structure model” for the conformation of the complementarity-determining regions of antibodies, and they applied this model to the analysis of antibody-germ-line genes, including the prediction of the structure of the corresponding proteins. This work has supported the “humanization” of antibodies for therapy in the treatment of cancer. “This approach to cancer therapy is based on the observation of H. Waldmann that rats can raise antibodies against human cancers, but that the rat antibodies lead to immune responses, similar to allergies, in human patients,” Lesk explains. “Humanization of these antibodies is the formation of hybrid molecules that are more human than rat, but that retain the therapeutic activity while reducing the patient’s immune response.”
Lesk’s work also involves the detailed comparison of proteins in different structural states as a means for understanding the mechanisms that enable the proteins to change conformation, both as part of their normal activity and in disease. The discovery and analysis of these mechanisms was the key to understanding conformation changes in serine protease inhibitors, also known as serpins, mutations of which are an important cause of several diseases, including emphysema and certain types of inherited mental illness.
Lesk used a systematic analysis of protein-folding patterns to develop a mathematical representation that aids in the recognition and classification of these patterns. He also wrote the first computer program to generate schematic diagrams of proteins using molecular graphics, and he developed many algorithms now used by other researchers to analyze the structures of proteins.
Lesk was formerly chair of the Task Group on Biological Macromolecules for the Committee on Data for Science and Technology (CODATA), which aimed to foster worldwide coordination of databases in molecular biology to enhance their quality and utility. He has given invited lectures and presentations related to his research at universities and professional conferences worldwide.
Lesk is a member of the American Physical Society
American Physical Society
The American Physical Society is the world's second largest organization of physicists, behind the Deutsche Physikalische Gesellschaft. The Society publishes more than a dozen scientific journals, including the world renowned Physical Review and Physical Review Letters, and organizes more than 20...
. He has published 189 scientific articles and 10 books related to his research
.
Prior to joining Penn State during the fall semester of 2003, Lesk was on the faculty of the clinical school at the University of Cambridge from 1990 to 2003. He was a group leader in the biocomputing program at the European Molecular Biology Laboratory in Heidelberg, Germany, from 1987 to 1990; a visiting scientist at MRC Laboratory of Molecular Biology in Cambridge, United Kingdom, between 1977 and 1990; and a professor of chemistry at Fairleigh Dickinson University in New Jersey from 1971 to 1987. He has held visiting fellowships at the University of Otago in New Zealand and Monash University in Australia. He also is a Life Member of Clare Hall at the University of Cambridge in the United Kingdom.
Along with Karl D. Hardman, Lesk wrote the first computer program
Computer program
A computer program is a sequence of instructions written to perform a specified task with a computer. A computer requires programs to function, typically executing the program's instructions in a central processor. The program has an executable form that the computer can use directly to execute...
for generating the schematic diagram of protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. It is known to produce one of the most effective representations of the protein structures and employs the classification scheme for Ribbon Diagrams created by Jane Richardson. Although these schematic diagrams are less detailed compared to the other representations, such as, picture stimulating wire models or space-filling models, it is more effective in presenting the topological relationships among elements of secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, due to its simplistic structural expression. This was then further improved by creating a program to produce stereoscopic pairs of diagrams. As a result, the viewer’s ability to perceive spatial relationship in complex molecules was enhanced.
Lesk received a bachelor’s degree, magna cum laude, from Harvard University in 1961. He received his doctoral degree from Princeton University in 1966. He also received a master’s degree from the University of Cambridge in the United Kingdom in 1999.
Operation of the program
The basic operation of the program begins with the execution of line drawing. There are four phases involved in this program:- The input phase – Program reads the input files. There are two input files. They are the coordinates and the details of the contents and appearance of the picture.
- Picture generation – Geometric transformation of coordinates are generated by the program into picture elements. For example, a cylinderCylinder (geometry)A cylinder is one of the most basic curvilinear geometric shapes, the surface formed by the points at a fixed distance from a given line segment, the axis of the cylinder. The solid enclosed by this surface and by two planes perpendicular to the axis is also called a cylinder...
of appropriate size and orientation about the z-axis represents α-helix; each peptidePeptidePeptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
plane is determined for Ribbon Diagrams and β-sheets; and splineSpline (mathematics)In mathematics, a spline is a sufficiently smooth piecewise-polynomial function. In interpolating problems, spline interpolation is often preferred to polynomial interpolation because it yields similar results, even when using low-degree polynomials, while avoiding Runge's phenomenon for higher...
fit is used for curved sheets. - Hidden-line removal – This step is only required by the cylinders of α-helices and the arrows of β-sheets, not skeletal models. Picture of these structures are classified by three levels of “optical density” – transparent, translucent, or opaqueOpacity (optics)Opacity is the measure of impenetrability to electromagnetic or other kinds of radiation, especially visible light. In radiative transfer, it describes the absorption and scattering of radiation in a medium, such as a plasma, dielectric, shielding material, glass, etc...
. If lines are passing behind the transparent object, it is not changed. If it passes behind a translucent object, it is altered into dashed lines. If it is opaque, the lines passing through the object are removed completely. This step can be replaced with an alternative step to create a Colour-Raster Output. The lines are ignored and the windows are painted according to the user. - Output – Character strings are extended to sets of line segments through a set of stroke tables. Line segments are placed into the two dimensional space.
Miscellaneous
Arthur Lesk's son, Victor Lesk has followed his father into the field of structural biology and bioinformatics, and currently holds a post-doctoral research position with Michael Sternberg at Imperial College LondonImperial College London
Imperial College London is a public research university located in London, United Kingdom, specialising in science, engineering, business and medicine...
.