HERE IN THIS PRESENTATION HY HOMOLOGY MODELING IS EXPLAIN , WITH EXAMPLES OF PROTEIN PRIMARY AND SECONDARY, SHOWING THE IMAGES FORM WHICH MAKES EASY TO UNDERSTAND
Prediction of the three dimensional structure of a given protein sequence i.e. target protein from the amino acid sequence of a homologous (template) protein for which an X-ray or NMR structure is available based on an alignment to one or more known protein structures
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein.
Image result for homology modeling
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein (the "template").
Prediction of the three dimensional structure of a given protein sequence i.e. target protein from the amino acid sequence of a homologous (template) protein for which an X-ray or NMR structure is available based on an alignment to one or more known protein structures
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein.
Image result for homology modeling
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein (the "template").
Ab Initio Protein Structure Prediction is a method to determine the tertiary structure of protein in the absence of experimentally solved structure of a similar/homologous protein. This method builds protein structure guided by energy function.
I had prepared this presentation for an internal project during my masters degree course.
The experimental methods used by biotechnologists to determine the structures of proteins demand sophisticated equipment and time.
A host of computational methods are developed to predict the location of secondary structure elements in proteins for complementing or creating insights into experimental results.
Chou-Fasman algorithm is an empirical algorithm developed for the prediction of protein secondary structure
Structure based drug design- kiranmayiKiranmayiKnv
This presentation helps in detail learning about the structure based drug design. It includes types of structure based drug design and detailed study of docking, de novo drug design.
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
Ab Initio Protein Structure Prediction is a method to determine the tertiary structure of protein in the absence of experimentally solved structure of a similar/homologous protein. This method builds protein structure guided by energy function.
I had prepared this presentation for an internal project during my masters degree course.
The experimental methods used by biotechnologists to determine the structures of proteins demand sophisticated equipment and time.
A host of computational methods are developed to predict the location of secondary structure elements in proteins for complementing or creating insights into experimental results.
Chou-Fasman algorithm is an empirical algorithm developed for the prediction of protein secondary structure
Structure based drug design- kiranmayiKiranmayiKnv
This presentation helps in detail learning about the structure based drug design. It includes types of structure based drug design and detailed study of docking, de novo drug design.
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
Proteins : is made of chain of amino acids ( amino acid= monomers) therefor the protein is polymers .
The proteins are made up of carbon, hydrogen, oxygen, and nitrogen.
Amino acid :
protein structure prediction methods. homology modelling, fold recognition, threading, ab initio methods. in short and easy form slides. after one time read you can easily understand methods for protein structure prediction.
MUTUAL PRODRUG IS DISCUSSED HERE IN DETAIL WITH ITS MULTIPLE TYPES AND FUCTIONAL GROUPS IT IS USE FOR AND FAILURE WITH PRODRUGS, WITH PHARMACEUTICAL EXAMPLES AND STRUCTURE ARE ALSO SHARE, SYNTHETIC APLLICATIONS.
HERE PRESENTS AN OLIGONUCLEOTIDE THERAPY, ITS INTRODUCTION TO OLIGONUCLEOTIDE, ITS TECHNIQUES, DEVELOPED METHODS AND THEIR APP,LICATIONS IN PHARMACEUTICAL ARE HERE DISCUSSED IN DETAIL
OXIDATION [PHARMACEUTICAL PROCESS CHEMISTRY]Shikha Popali
INTRODUCTION TO OXIDATION , WHICH IS PROCESS OF ADDITION OF OXYGEN TO THE COMPOUND IN RPOCESS CHEMISTRY AND LIQUID PHASE OXIDATION AND OTHER OXIDISING AGENTS ARE DISCUSSED.
Synthetic reagent and applications OF ALUMINIUM ISOPROPOXIDEShikha Popali
SYNTHETIC REAGENTS AND APPLICATIONS OF ALUMINIUM ISOPROPOXIDE ITS ALTERNATIVE NAMES AND ITS PHYSICAL PROPERTIRS , HANDLING, STORAGE, PRECAUTIONS, PREPARATIONS, SYNTHETIC APPLICATIONS
PTC IS THE PHASE TRANSFER CATALYSIS HERE TYPES OF PTC ARE DISCUSSED , THEORIES OF CATALYSIS AND MECHANISM OF PTC, ADVANTAGES OF PTC, APPLICATION OF PTC
SWERTIA CHIRATA NATURAL PRODUCT OF PHARMACEUTICALSShikha Popali
HERE THE NATURAL PRODUCT SERTIA CHIRATA IS DISCUSSED WITH ITS COMMON NAME, CHEMICAL CONSTITUENTS, ACTIVE CONSTITUENTS, SAR, MEDICINAL ACTIVITY AND MORE
THE DCC I.E. DICYCLOCARBODIIMDE IS A REAGENT AND HERE THE DETAIL ACCOUNT ON IT IS GIVEN INCLUDING MOLECULAR WEIGHT, STRUCTURE, SYNTHESIS AND PHYSICAL PARAMETERS AND APPLICATIONS FOR OTERS SYNTHESIS ARE ALSO DISCUSSED, THE DIFFERENT SYNTHESIS WITH DCC COMBINATION ARE ALSO MENTIONED
COMPARATIVE EVALUATION OF DIFFERENT PARACETAMOL BRANDSShikha Popali
THE PARACETAMOL TABLETS IS COMMONLY TAKEN AND PRESCRIBED FOR FEVER , SO HERE WE HAVE MADE PRACTICAL IS IT TRUE EVALUATION LABEL AND WHICH BRAND IS MORE SAFE.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists
HOMOLOGY MODELING IN EASIER WAY
1. Tertiary Structure Prediction Methods
Any given protein sequence
Structure selection
Compare sequence with proteins have solved structure
Homology
Modeling
> 35%
Fold
Recognition
ab initio
Folding
< 35%< 35%
Structure refinement
Final Structure
Structure selection
2. Why Homology modelling ?
X-ray Diffraction
– Only a small number of proteins can be made to form crystals.
– A crystal is not the protein’s native environment.
– Very time consuming.
NMR Distance Measurement –
– This method generally looks at isolated proteins rather
than protein complexes.
– Very time consuming
3. Homology Modeling:
Principles, tools and techniques
• Development of molecular biology: rapid
identification, isolation and sequencing of genes.
• Problem : time-consuming task to obtain the 3D-
structure of proteins.
• Alternative strategy in structural biology is to
develop models of protein when the constraints
from X-ray diffraction or NMR are not yet
available.
• Homology modeling is the method that can be
applied to generate reasonable models of protein
structure.
4. Database approach to homology modelling
As of June 2000, 12,500 protein structures have
been deposited into the Protein Data Bank (PDB)
and 86,500 protein sequence entries were contained
in SwissProt protein sequence database.
• This is a 1:7 ratio – relatively few structures are
known.
• The number of sequence will increase much faster
than the number of structures due to advances in
sequencing.
5. Sequence similarity methods
• These methods can be very accurate if there is > 50%
sequence similarity.
• They are rarely accurate if the sequence similarity < 30%.
• They use similar methods as used for sequence alignment
such as the dynamic programming algorithm, hidden
markov models, and clustering algorithms.
6. What is Homology Modeling?
• Predicts the three-dimensional structure of a given protein sequence
(TARGET) based on an alignment to one or more known protein structures
(TEMPLATES)
• If similarity between the TARGET sequence and the TEMPLATE sequence
is detected, structural similarity can be assumed.
• In general, 30% sequence identity is required for generating useful models.
7. Structural Prediction by Homology Modeling
Structural Databases
Reference Proteins
Conserved Regions Protein Sequence
Predicted Conserved Regions
Initial Model
Structure Analysis
Refined Model
SeqFold,Profiles-3D, PSI-BLAST, BLAST & FASTA, Fold-recognition methods (FUGUE)
Cα Matrix Matching
Sequence Alignment
Coordinate Assignment
Loop Searching/generation
WHAT IF, PROCHECK, PROSAII,..
Sidechain Rotamers
and/or MM/MD
MODELER
8. How good can homology
modeling be?
Sequence Identity
60-100% Comparable to medium resolution NMR
Substrate Specificity
30-60% Molecular replacement in crystallography
Support site-directed mutagenesis
through visualization
<30% Serious errors
9. Significance of Protein Structure
What does a structure offer in the way
of biological knowledge?
Location of mutants and conserved residues
Ligand and functional sites
Clefts/Cavities
Evolutionary Relationships
Mechanisms
10. The importance of the sequence
alignment
• the quality of the sequence alignment is
of crucial importance
• Misplaced gaps, representing insertions or deletions,
will cause residues to be misplaced in space
• Careful inspection and adjustment on Automatic
alignment may improve the quality of the modeling.
11. Programs for Model Protein
Construction
• MODELLER 4.0
– guitar.rockefeller.edu/modeller/modeller.html
• SWISS-MOD Server
– www.expasy.ch/swissmod/SWISS-MODEL.html
• SCWRL (SideChain placement With Rotamer Library)
– www.fccc.edu/research/labs/dunbrack/scwrl/
12. Protein Structural Databases
• Templates can be found using the TARGET sequence as a
query for searching using FASTA or BLAST
– PDB (http://www.rcsb.org/pdb)
– MODELLER
(http://guitar.rockefeller.edu/modeller/modeller.html)
– ModBase (http://pipe.rockefeller.edu/modbase/general-
info.html)
– 3DCrunch
(http://www.expasy.ch/swissmod/SM_3DCrunch.html)
13. Gaining confidence in template
searching
• Once a suitable template is found, it is a good idea to do
a literature search (PubMed) on the relevant fold to
determine what biological role(s) it plays.
• Does this match the biological/biochemical function
that you expect?
14. Other factors to consider in selecting
templates
• Template environment
– pH
– Ligands present?
• Resolution of the templates
• Family of proteins
– Phylogenetic tree construction can help find the
subfamily closest to the target sequence
• Multiple templates?
15. Target-Template Alignment
• No current comparative modeling method can recover
from an incorrect alignment
• Use multiple sequence alignments as initial guide.
• Consider slightly alternative alignments in areas of
uncertainty, build multiple models
• Sequence-Structure alignment programs
– Tries to put gaps in variable regions/loops
• Note: sequence from database versus sequence from
the actual PDB are not always identical
16. Target-Multiple Template Alignment
• Alignment is prepared by superimposing all
template structures
• Add target sequence to this alignment
• Compare with multiple sequence alignment and
adjust
17. Adjusting the alignment
• Using tools such as Joy (www-cryst.bioc.cam.ac.uk/~joy/)
to view secondary structure along the alignment and use this information as
criteria for adjustments
• Avoid gaps in secondary structure elements
0 * 240 * 260 * 280 *
1ad3 : LKPSEVSGHMADLLATLIPQY-M---DQNLYLVVKGGVPETTELLK--ERFDHIMYTGSTAVGKIVMAAAAK- : 200
1cw3 : MKVAEQTPLTALYVANLIKEAGF---PPGVVNIVPGFGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSS : 254
1ad3_4 : LKPSEVSGHMADLLATLIPQY-M---DQNLYLVVKGGVPETTELL--KERFDHIMYTGSTAVGKIV-MAAAAK : 200
1cw3_4 : MKVAEQTPLTALYVANLIKEAGF---PPGVVNIVPGFGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSS : 254
1ad3_5 : LKPSEVSGHMADLLATLIPQY-M---DQNLYLVVKGGVPETTELLKER--FDHIMYTGSTAVGKIV-MAAAAK : 200
1cw3_5 : MKVAEQTPLTALYVANLIKEAGF---PPGVVNIVPGFGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSS : 254
1ad3_6 : LKPSEVSGHMADLLATLIPQY-M---DQNLYLVVKGGVPETTELLKER--FDHIMYTGSTAVGKIV-MAAAAK : 200
1cw3_6 : MKVAEQTPLTALYVANLIKEAGF---PPGVVNIVPGFGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSS : 254
1ad3_ce : LKPSEVSGHMADLLATLIPQYM----DQNLYLVVKGGV-PETTELLKE-RFDHIMYTGSTAVGKIVMAAAA-K : 200
1cw3_ce : MKVAEQT---PLTALYVANLIKEAGFPPGVVNIVPGFGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSS : 254
6K E 3 a a 6i 6 6V G p 6 D 6 5TGST 6G466 AA
18. Secondary Structure Prediction
The Predict Protein server
http://www.embl-heidelberg.de/predictprotein/
Adding secondary structure prediction algorithms can
help make decisions on whether helices should be
shortened/extended in areas of poor sequence identity.
PHD program
19. Constructing Multi-domain protein models
• Building a multi-domain protein using templates
corresponding to the individual domains
• proteinA aaaaaaaaaaaaa---------------------
• proteinB -----------------bbbbbbbbbbbbbbb
• Target aaaaaaaaaaaaabbbbbbbbbbbbbbb
20. Multiple model approach
Reminder: Consider the effects of different substitution
matrices, different gap penalties, and different
algorithms. (Vogt et al. J. Mol. Biol. 1995, 249:816-
831.)
Construct multiple models
Use structural analysis programs to determine best
model
Jaroszewski, Pawlowski and Godsik, J. Molecular Modeling, 1998, 4:294-309
Venclovas, Ginalski and Fidelis. PROTEINS, 1999, 3:73-80 (Suppl)
21. Model Building
• Rigid-Body Assembly
– Assembles a model from a small number of rigid bodies
obtained from aligned protein structure
– Implemented in COMPOSER
• Segment Matching
• Satisfaction of Spatial Restraints
– MODELLER
– guitar.rockefeller.edu/modeller/modeller.html
22. Modeller
• Main input are restraints on the spatial structure of AA and ligands to be
modeled.
• Output is a 3D structure that satisfies these restraints
• Restraints are obtained from related protein structures (homology modeling)
- obtained automatically, NMR structures, secondary struture packing and
other experimental data
23. What are the Restraints ?
distances, angles, dihedral angles, pairs of dihedral angles and
some other spatial features defined by atoms or pseudo
atoms.
24. Sidechain Conformation
• Protein sidechains play a key role in molecular
recognition and packing of hydrophobic cores of
globular proteins
• Protein sidechain conformations tend to exist in a
limited number of canonical shapes, usually called
rotamers
• Rotamer libraries can be constructed where only
3-50 conformations are taken into account for
each side chain
25. Sidechains on surface of protein
• Exposed sidechains on surface can be highly flexible
without a single dominant conformation
• So ultimately if these solvent exposed sidechains do not
form binding interactions with other molecules or
involved in say, a catalytic reaction, then accuracy may
not be crucial—also look at the B-factors
• Can refine the sidechains with molecular mechanics
minimization
– Sampling?
– Scoring?
26. Errors in Homology Modeling
a) Side chain packing b) Distortions and shifts c) no template
27. Errors in Homology Modeling
d) Misalignments e) incorrect template
Marti-Renom et al., Ann. Rev. Biophys. Biomol. Struct., 2000, 29:291-325.
28. Detection of Errors
• First check should include a stereochemical check on
the modeled structure—PROCHECK, WHATCHECK,
DISTAN– which will show deviations from normal
bond lengths, dihedrals, etc.
• Visualization– follow the backbone trace and then
subsequently move out to Cα-Cβ orientation.