Ind ian Jl1 urn :ll o f Chemi,try Vol. 3~B. DelTlllher I!J!J!J. pp . 1.149-1358

A physicochemical approach to interpret the biological activities of some dipeptide systems

Kh M E Hashem *, F A-E-A Ali & MAT Ibrahim'

C hemis try Dept. , Facu lty of Science. Ain-Shams Uni versity . Cairo, Egypt

+Applied Mathematics Dept. . Facu lty of Science . Ai n-Shams Univers it y. Cairo, Egypt

Received 21 October 1997; accepted (revised) 16 April 1999

The hiol ogical activities of four iso- ni cotinoyl dipeptide systems are attributed to so me physicochemical parameters. The se mi -empirical M DO toget her with the AM I methods , have been appli ed to define these parameters by optimizing the structural energy o f the fou r systems wi th respect to incremental variation of their backbone dihedral angles. The lowest

energetic structures a re determined by generating two ECD maps by plotting $1 1 vs 'VI I and 'V I I vs $2 1 dihedral angles for each of the four sys tems. The co mpari son between the lowest energe ti c struc tures reveals that these systems have permanent Jipol e mo ments. Based (m the different susceptibilities of the dipeptide tail s to rotate as bonded charged masses around the X-axi s of the mo lecular frame . the Gaussian cylinders characteristic by nine different charged zones could be specul ated . The , ign o f thc residual charges on the zones corresponJing 10 the backbone's bonJs and side chai n residues, which are labcled ,ccti OIl 2. are defined as the required physicochemi cal parameters . It appears that the biological activit y of each sys tem i, affected hy the sign of the charges all ocated on the above section of each sys tem. If the charge is +ve then the corn .. <sponding dipeptide sys tem(s) should possess biological ac tivities . otherwise the sys tem(s ) are biologically inactive.

The identificati on o f the primary structure , of a peptide via a spec ifi c structural parameter which was

- ' 1\ se lec ted trom the . CN MR spectrum for 28 common amino ac ids, was the target of our earlier workt. One of the current problems is the in vestigation of the rebt ionsh i ps between the secondary structure and biological function of a peptide2. A set of peptides tould be se lec ted as a representative mode l' , if the following criteria are ach ieved : ( i) the peptides have structural s imilarity , ( ii ) the peptides possess differen t bi o logica l affinities. A set of four simple dipeptides. named iso-ni cotinoy l-Lx J-Lx2 methyl ester. was se lec ted from the lite ratilre to be a mode l4

for the present study . The ir structures (Figure 1) are classified to head and tail. Hereafter , the four dipeptides arc ca lled a . b , c and d , as g iven in Table I where the dipeptides band d actually possess biol og ica l ac t i viti es towards Pseudo/l/onas (l erllgll/OSe, Cal/dida II/ilis, Candida alhic([l/s and Sperg illlls I/ig('/'~ While dipeptides a and c are b iologica ll y inacti ve towards the sa me organi sms~.

The main target o r the present study is to dete rmine the ph ys icoc hemica l parameter(s) upon whic h the v,lria ti on o f the ir biologica l ac tiv ities could be inte rp reted .

Experimental Section Starting geometries

The four ex tended structures of the dipeptide

syste ms are shown in figures l(a-d). The atoms' type sche me and symbolic nomenclature are li sted in

Table II. The ex tended structures are partitioned to head (nicotinoyl nucleus), tail (dipeptide amino ac ids) and end group (methyl es te r). ( i) The structure of the nicotinoy l moiety is pl anar with fixed bond lengths and angles). The Cartes ian origin of the molecular frame was fixed to co inc ide with C 141 , while the X-

axis was aligned wit h CI~ I--C *171 bond , (i i) The initial secondary struc tures of the first and second amino acids of the four tai Is were pertained as previously published6

. ( iii ) Due to the uncertainties in the pos ition of the hydrogen atoms , they are neg lected from the numbering syste m. ( iv) The tetrahedral ang les of the te rminal methyl of the end group is assumed typica l. The non-hydrogen atoms of the end group are not cons idered as backbone atoms. (v) Rotati on of the dipepti de ta il around the X-axis was the onl y rota ti o nal moti on considered . (vi) Although , the peptide groups have the ir own pl anar structures due to the loca l ized resona nce. yet, the co-p lanarity between them ill eac h sys tem was not achi eved .

1 ~ 50 INDIAN J CHEM, SEC B, DECEMBER 1999

b Isonicotinoyl L-Valine-L-Leucine methyl ester

'"

d

(9) Nitrogen atom ( I 0) Carbon atom (15) Oxygen atom

Is6nicotinoyl L-Valine-L-Tyrosine methyl ester ".,

( 12) I'/itrogen atom (3) Carbon atom (8) Oxygen atom

, ..

a isonicotinoyl L-Valine-L-Valine methyl ester

c

( I ) Nitrogen atom (4) Carbon atom (33) Oxygen atom

Isonicotinoyl L-Valine-L-Serine methyl ester

(12) Ni trogen atom (14) Carbon atom ( 16) Oxygen atom

Figure I - Extended structures of the four dipept ide monomers

DipqJliLic sy mhol (monumer)

Head

Table I- Four dipeptides

I " amino acid 2"J amino acid Lx z

End Group EG L XI

a

h

d

iso-nicotinoyl

iso- ni cotinoyl

iso-nicotinoyl

iso-nicotinoyl

vali ne

valine

valine

valine

valine

lellcine

seri ne

tyrosine

methyl ester

methyl ester

methyl ester

methyl ester

Molecular potential energy (A) Intramolecular potential energy

T he calcul ated e lec trostati c pa ir-wise, repul sive non-bonded types 1-4 and 1-5 and hydrogen bond inte racti ons a re summed for each new generated Isomer to eva lu ate its intramolecul ar potentia l energ/ . To reduce the computati onal time during the ca lcu lati on o f the intramolecular potentia l energy, the fo ll ow ing se lec ti on rules a re applied ; ( i) During the ca lcul ati on o f e lec tros tati c pair-wise interaction, cut off d istances greate r than 12A are imposed. ( ii ) For repu lsive non-bonded ' 1-4 and 1-5 inte ractions, di stances greater than van der W aal's radii plus 4A are rejec ted. ( iii ) Tors ional energtes assoc iated with

rotati on around the parti a l It-bond(s) are not consi dered.

(B ) Intermolecular potential energy Based on the polari zabilities of the four dipeptide

systems, the inte rmo lecul ar potentia l energ ies, in te rms of London attracti on di pole-dipole ene rgies, are explo red . T he fo ll owing selecti on rules are applied during the calc ul ati ons; (i) The length of each di peptide tai l ( R. ). is defined as the sum of bond length s be tween N2[9] atom of the first amino ac id and the furthest atom of the second amino ac id pl us the van de r Waal 's radius of the furthest atom. ( ii ) London attrac ti on energy is iterat ive ly calcul ated

/I

.,. -

-

HASHEM et at.: STUDY OF BIOLOGICAL ACTIVITIES OF DIPEPTIDE SYSTEMS 1351

Table II-The one atom type scheme and the symbolic nomenclature of each type

Carbon (C)

Symbols Cha mc ters

C2

CA

sp ' Carbon with two H

sp' Carbon wi th three H

s p~ Aromatic carbon in six lIle lllber ring with one H

C* s p' Carbon with one H

C' s p~ Aromatic carbon in s ix lIle mber ring with one suhstituent

C · sp: Carbonyl carbon and arnll1atic carbon with hydroxyl substituent in tyrosine

Nitrogen (N)

Symbols Characters

N*

N2

Sp2 Nitrogen in six member ring with lone pairs

Sp2 Nitrogen attached with carbonyl group

within the bounded range of (R to R+4A) by using the inverse sixth power of R assuming that the temperature is constant. (iii) When the distance between two monome rs is very large, induce-dipole interac ti on energies are ca lculated by using two point charge vec tors.

Sequence of computational analysis Assuming that eac h iso-nicotinoyl dipeptide

molecule exists in a monomer state, two optimization cycles are designed to generate numerous structural

. . b . h I f I I I transitions y varylllg t e va ues 0 <I> I vs. \jI I and \jI I

vs. <1>11 backbone dihedral angles . The I st optimization cycle for the four dipeptide systems is initiated when

C *l lor-C*111 1 bond lies in or parallel to the X-V plane of the mo lecular frame. For each structural variation , the partial charges on the hydrogen and non-hydrogen atoms, are computed hy applying the semi-empirical molecular orbi tal methods named Minimum Neglect of Differential Overlap " MNDO" and Austin Model I "AM I" , to evaluate the molecul ar potential energy of the generated isome r~- 15. The values of the backbone

dihedral angles <1>1 I and \jI1), at which the lowest energetic structures are achieved, is the criteria by which the first optimization cycle was terminated. On the basis of van der Waal's radii and triangle sum rules l6, a set of constraints was proposed to select one of the generated structures as a starting geometry for the second optimization cycle.

Hydrogen (H)

Symbols Characters

H*

H

Hydrogen attached with carbon

Hydrogen attached with nitrogen

Hydrogen attached with oxygen

Oxygen (0)

Symbols Characters

0 ' Carbonyl oxygen

Ester oxygen

Alcohol oxygen

The initiation of the second optimization cycle is

conditioned by ; (i) The optimized value of <1>1 I dihedral. angle is kept constant from the first cycle.

(ii) The corresponding value of \jI1 I was introduced as

initial input in a nested do loop with the full

incremental scale of <1>21. The second optimization cycle was terminated by determining new values for

\jI1 I and <1>21 which produce the lowest energetic

structure. At the end of each optimization cycle the sum of the computed intra- and intermolecular potential energies for each generated structure, were plotted in the form of Energy Contour Diagrams

(ECD).

Determination of the charge densities on the Gaussian cylinders' surfaces

The four dipeptide tails are treated as non­vibrational bonded syste ms which freely rotate around the X-axis to produce Gaussian cylinders after a whole rotation cycle l7 The densities of the formed charges on the surface of the Gaussian cylinder of each tail are calculated on the basis of the charge per

unit area (AlA2), cylinder radius (rA) and cylinder length (LA). The produced Gaussian cylinders' surfaces of the different tails are divided into nine fixed zones named in order el

), e2), <1>1), \jI1), (01), <1>2),

~I' 0/1 and EG. The charges on the nine zones are divided into three sections . Sections 1 and 3 represent

1352 INDIAN J CHEM, SEC B, DECEMBER 1999

zones I and 9 respectively, while section 2 includes the zones from 2 to 8.

Results and Discussion Type, number and length of each bond in the

structures of the four dipeptide systems are listed in Table Ill . The ECD maps of the a, b, c and d dipeptide systems at the end of the first optimization cycle are plotted in Figure 2A. Each ECD map includes four lowest minIma, however, this phenomenon supports the similarity be tween the structures of the four optimized dipeptide systems. The lowest energetic structures deduced from the

ECD maps are: <1>11=170°, \jI1,=65° ; <1>',=175°, \jI',=50"

; <1>' j = 1500 , \jI ', =48" and <1>',=60°, \jI',=60° for a, b, c

and d dipeptide sys tems respectively . Although, the a­he lical structure cannot ex ist in a s imple dipeptide molecule, however, the appearance of a low energetic

conforme r at <1>1,=60" and \jI1 ,=60" for system d

nominating the ex istence of a low helical structure due to the phenolic ring o f tyros ine' S. However, it has been noticed that the value of the highest computed ene rgies within the first optimization cyc le overall the systems are above 140 Kcallmole.

Table IV shows the optimized values of the

struc tural parameters \jI1, and <1>21 backbone dihedral angles at the end of the 2nd optimization cycle. The lowest energe ti c structures for a. b , c and d

monomers a re spotted at \jI',=70°, <1> 2,= 160°; \jI ', = 60" n-, " =60"· '-90" ,1.2 =90°' 111' _8S tJ n-, 2 =95° , 't' I , '-V 1- , \j.J I , 't' 1- ,'t' I

Table III-Number and types of bonds and their lengths in respect to the one atom scheme

Types of bonds and their lengths

Symbol s Cl-C2 C2-C* C\C' C'-C* Bond

i<:nglh A 1.53 1.47 1.42 1.53

a 4 4

h 4 2 4

c 2 4

d 2 4

Symhols C*-I 2 C*-N2 C*-O' Bond

Length A 1.46<) 1.125 1.23 1.35

a :2 2 3

h 2 2 3 l' 2 2 3

J 2 2 3

C2-CA

1.53

1.425

C*-C*

1.53

2

CA-O"

1.36

c-c

1.53

2

2

2

2

N2_H*

1.014

2

2

2

2

C3- H' C2- H' CA-H' C'- N*

1.09 1.09 1. 297

5

5

3

3 4

Oh_H CA-CA C'-H' C2-011

0.96 1.42 1.085 1.312

4

4

4

6 4

Tanlc IV- Resu lt s of the seco nd optimi zati on cycle by varying ljIi vs ¢12 using semi-empiri cal MNDO together with AM I methods

Amino Co nfiguration of the energ~ minima regions acid 2 3

residues 1jI ,I ¢I" Energy Kca l/mo l* ljIi ¢12 Energy Kcallmol* IjIII ¢1

2 Energy Keal/mol*

Min Max Min Max Min Max

ta) Val-Val 70 160 0 90 170 15 2.4 <)0 120 95 5.4 90

( h )

V;II- Lcu 60 60 0 120 149 155 6.7 120

(e)

Val -Scr YO <)0 0 75 130 40 2.9 75 115 140 7.5 75

t tll Val-Tyr R5 ')5 0 120 150 85 7.5 120

The clll;rgies ;11\; in unit s of Kcallmole relative to zero at the lowest energy minimum.

•

HASHEM el at.: STUDY OF BIOLOGICAL ACT IVITIES OF DIPEPTIDE SYSTEMS 1353

monomer! monomer ~

110 leo

1110 110

100 110

UO 170

100 100

\VI \VI eo I 80 I

10 110

40 '0

20 ~O

0 16 XI 46 DO 0

76 110 106 120 1:16 160 166 160 16 XI '6 DO 76 go 106 170 136 160 166 l eo

~I I

monomer h monomer !! 180 1110

1110 160

140 140

'20 170

100 100

\VI I 80 \VI

I eo

10 DO

'0 '0

20 70

o o

~I I

~I I

Figure 2--Energy Contour Diagrams (ECD) at the end of the 1st optimi zation cyc le to optimize", i vs ¢i

respectively . The number of energy minima for monomers a , b , c and d , are 3, 2, 3 and 2, respectively . The values of the highest computed energies at the end of the 2nd optimization cycle were computed as 90, 120, 75 and 120 Kcallmole for a, b , c and d monomers, respect ive ly. The depress ions of these final optimized values of the maximum energies than that firstly optimized are 50, 20, 65 and 20 Kcallmole for a , b , c and d systems, respectively. These depress ions indicated that ; (i) The capability of the 2nd optimization cycle, to. refine the optimum

dipeptide structures of the first cycle. ( ii ) The a­helical structure of b system could be confirmed, where the final refined values of both \jI '1 and <1>2, dihedral angles are equal to 60°. (iii) The energies of the optimized structures and. number of energy minima, after the second optimization cycle, of monomers b and d are similar to each other, but differ than monomers a and c, which are, also, similar.

Figure 2B decla res the ECf) 's of the 2nd optimi­

zati on cyc Ie to optimize \ji ll vs. <1>21.

Table V indicates the fina l set of the computed partial charges· on the hydrogen and non-hydrogen atoms of the four dipeptide systems, from which the lowest potenti al energies corresponding to the optimum va lues of \jI's and <1> 's dihedral angles are calcul ated . The fo ll ow ing remarks were deduced from the computed parti a l charges;

( i) The C21n l of leuc ine and tyros ine side chain of

band d mo lecules have parti al charges - 0.033 and

-0.05 ecu respective ly, whi le the same atom of serine in molecule c ex hibits pos iti ve partial charges +0.139

ecu . So, the part ia l charge on Cp atom of saturated side chain re fl ects the polarity on the subsequent

atoms; be ing slightly negative if Cy atom is carbon and becomes positive if Cy is oxygen.

(ii ) The net partial charges on C r2), C r:1 ) and C r4) were computed as -0 .058, -0.132 and -0.075 ecu

1354 INDIAN J CHEM, SEC B, DECEMBER 1999

monomer ~

monomer ~ 160 ,--r----r-----------..----

106

gO

76

00

o 16 30 '6 00 16 90 106 120 136 160 1M l BO o 16 30 '6 00 76 gO 106 120 136 lOa 100 lec

monomer Q 160

10 1 monomer Q

16'

1'1

I \VI

126

116

102 -

eg

70

03

60

16 00 ' 6 00 16 gO 106 120 13b 160 106 lBO a 16 30 ' 6 60 n gO 106 120 136 160 106 lOa

Figure 2B- Energy Contour Di agrams (ECD) at the end of the 2nd optimizati on cycle to optimi ze 'I' ll YS ¢12

respectively . These values are in full agreement with the resonance rule on pyridine ring . Howe ver, the polarity of the nicotinoyl head could be attributed to the separate contributions of both localised resonance

on pyridine ring and --C- N --C moie ty. II o

(iii ) The constancy of the calculated partial charges' values , on the hydrogen and non-hydrogen atoms of the first amino ac id of a ll systems, indicate

that the polarizab ility o f the iso-nicotinoy l head does not ex tend to the amino acids of each tail.

Table VI shows the computed values of the Gaussian parameters (L, rand ')J A 2) and the nine defined charged zones of each system. The foll owing remarks have been noti ced :

(i) The negative charges were resident on zones corresponding to the projections of the backbone's

bonds only. These bonds are C *rw -O'[8J' N2 r9r -C *[I OJ'

C*[I W-O' [15), N2[1 2r -C*[I' J and oe[33 ]--C3 [.14J.

T ahll' \ '-T he computeu charge ui,trihUl ion> fo r th .: li ned optimi zeu struct ures wh ich arc ca lcu lated by M NDO iogethcr wi th AM I methods

No. llf A tom>

2 3 4

5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 21 22 23 24 15 26 n 28 29 30 31

CI''''I -11 ,',11 1,) 11

P~ndll1 <:

ling.

C lrhonyl group

Back­

bone

Carbonyl

oxyge l1

First amino acid

sidc chai n

Second

amino

aciu side chain

chain

T~ pc ,) i'

.--\tOl1h

N C C C'

C

C' c' a' N2 C* C* N2 C* C· a' a' c· o C3 C· C* C2 C3 C3 0 " CA CA

CA

CA CA

CA

Charge uI'tnhut i,)11 ()\'cr th.: non-hydroge l1 atoms

a Ii - - c J

-5 16 - 123 - 155 -·75 - 155 - 123 ·no

-413

- 495 81

41 0 - 431

72 425 -·no -427

8

-72 -72

8

-72 -72

- 516 - 123 - 155 -75 - 155 - 123 470

- 413 - 495

81 410 - 431 72

425 - 430 - "427

8 -72 -·72

- 14 - 33 -75 -75

- 5 16 - 123

- 155 -75 - 155 - 123 470

- 413 - 495

8 1 41 0 - 431 72

425 -430 - 427

8

-72 -72

139

-350

-5 16 -113 - 155 -75 - 155 - 123 470

- 41 3 - 495

81 410 -431 72

425 -430 -427

8 -72 -72

-50

35 -9 - 45 212 -45 -9

a

65 23

23 65

165 30

145 29

16 75 75 16

75 75

Charge di stribut ion

Charge 0 11 the au ac heu hydrogen atoms b -----c --------u

65 23

23 65

165 30

145 29

16 75 75

24 54 69 69

65 23

23 65

165 30

145 29

16 75 75

44

107

65 23

23 65

165 30

145 29

16 75 75

36

14 28

28 14

32 0" -3 10 135 33 End a -375 -375 - 375 - 375 34 group C3 -85 - 85 - 85 -86 78 78 78 78

(a) The located charges must be di vided by 10'\ to be in ECU (E lectron Charge U ni t)

(b) T he represented charges on all heavy ato ms don ' t i nclude the hydrogen charges.

(c) The ca lcul ated net charge i s the algebri c sum o f the charges on the cent ral atom and its attached hydrogen proton.

a

-5 16 -58

- 132 -75

- 132 -58 470 -4 13 -330 III 410 -286 101 425 -430 -427 24 3 3

24

3 3

-375 -7

Net part ial charge on the non-hydrogen alOms

15- - - - - [:----ll

-5 16 -58

- 132 -75

- 132 -58 470

- 4 13 -330 III 410 -286 101 425 -430 -427 24 3 3

10 21 -6 - 6

-375 - 7

-5 16 -58 - 132 -75 - 132 -58 470

- 413 - 330 III 41 0 -286 101 425 -430 -427 24 3 3

183

- 17

- 375 - 7

-5 16 - 58

- 132 -75 - 132 -5 8 470 -4 13 -330 III 410 -286 101 425 - 430 -427 24 3

3

- 14

35 5

- 17 212 - 17 5

-1 75 - 375 -7

No. or .au ac hed hydrogen

atoms

I 3 3

I 2 3 3

3

:r: » C/)

:r: tTl !:: ~

"" :--

C/)

-l C o -< o ..."

CO (5 r o o n » r » n -l

< j tTl C/)

o ..."

g "0 tTl "0 j o tTl C/)

-< C/)

-l tTl !:: C/)

w V1 V1

1356

r . r .

'" :"0 lJ -r

'" ~ 'J

'" 'J

EO

~ 0.:

1 ;...

-r "'", ("" - 00 tr)

.. '" \0 r"") N

tJ. ;::t; ~ ~ ~ ~, 6 0 0 0 fr. I I I I

b

~ ,.r, ('I 0\ -II") 0\ l"-

v . rr, r- ""', _ --: '0 r<1 00

r"'~o ooo

Ir. 0'> 1""", (' I

K_ lJ:! ;Z~~ vr.~' :=;cioo

~ G

C'-5- - :xJ -D ,... . rr, \0 0\

~ ,... ! ,.... . ("I ('I

/· 6000

'r,

, u

o

c- '" -~ 0 ,... , 1"""

Ooo~o8 o 0 I I I I

,..... 0-, 0-x ""', rr. ,.... . I""'l

'i;;,S:~, ~ 0' 999 T ;:-; z.

~ X 1"'1 ..0 ~ :::J Ir. rr. 'Xi

~ :=) 6 6 ;; I I I I

x -.0 - -r ,.,. , ~ 0'> ..... :

-r -r tr,

; ~ x

-¥LJ (i

U '0

on o .... 00 o 0-r-". o o

r­

'" oD 'r, r-". 00

o o

o 'r. ''1 on -r :; o

". ,.., 00 --r ,~.

r­o o o

on o -r 3 o

'" o

INDIAN J CHEM, SEC B, DECEMBER 1999

00 c ~ o u u "" ... OJ '0 C

;;., u

Howe ver, the diffe rences between the similar computed values of these negati ve charges o vera ll the four dipeptide monomers are due to the varia tion 111

the physical paramete rs of the Gauss ian cy linders .

( ii ) The pos iti ve c harges accommodated on the

projecti ons of C *[ IOr -C *[111> s ide c hain of the first

amino ac id, C *[ I.W-C *[141 and second amino ac id side chain bonds . The more de nse pos iti ve charges on the

C * C* h h h C * C * . zone [l3r- [141 rat e r t an t e zone [101-- [11 1 111

the systems are attributed to the po larity of the vicinal

oxygen atom o em) '

Figure III IS a schematic di agram that indicates the di stribut ion of the ca lcul ated res idua l c harges on the nine zones of the Gauss ian cy linders' surfaces of the four dipeptide sys te ms. The corre lation study be tween the three sections of the four Gau ss ian cy linders reveal s that; ( i) The al gebra ic sums of the res idual charges , overa ll three sec ti ons of each G auss ian cy linder's surface, for the fo ur sys tems, have approxi mate ly equa l numerical negative va lues

within ±O.O 168 ecu. This resurt ensures the struc tura l simil arity be tween the fo ur optimi zed monomers, ( ii ) The four dipeptide monomers are class ified as polar mo lec ul es. s ince the ir mos t stable lowest

energetic structures ex hibit two opposi te c harges. Quite o ft en. these two opposite charges (+ ve located on the head and -ve located in the cente r o f the ta il ) mu st be equa l to ac hieve the mo lecul ar neutra lity. The ex istence of these two permanent oppos ite c harges constitute a di pole mo ment. A verage dipo le mo ment pe r unit vo lume can be regarded as the c harge pe r un it a rea "po lari zati on". On the bas is of the va lues 01' the calc ulated po la ri zati on ecu/A. (cf Tahle VI) . the four dipeptide mo lecules a re arranged In the fo ll uw ing order; c > a > b > d . ( iii) The fo ur dipcptides could be c lass if ied to two groups accord ing to the seq uent ia l o rde r of the s Ign o f the pe rmanent ch arge on the head and three sec ti ons o f eac h ta il. T he c harac ter isti c sequence of the charge s ign o f the firs t group is a +ve charge on the head and contin uous -ve c harges on the ta il's three secti ons. Mono mers a and c be long to thi s group, whil e they ac tuall y ex hi bit bi o log ica ll y inacti ve properti es . Mono me rs band d ac tuall y ex hibit ac ti ve bi o logical prope r! ies . w h i Ie t h,'y were found to belong to the seco nd group whi ch IS c haracte ri zed by a di scre te c harge sequence as +ve, -ve, +ve and -ve. o n the head and the ta il 's th ree sec ti ons, respecti ve ly,

HASH EM el at.: STUDY OF BIOLOGICAL ACTIVITIES OF DIPEPTIDE SYSTEMS 1357

HonOM('r - 0.073\ ecu

- 1.6589 ecu

+ 0.2258 ecu Hononer

!!

1.6925 E'CU

Hononer

0.1395 ecu

- 1.6674 ecu

.. 0.4415 eeu

1.6817 ecu

Figure 3- A sc hematic dia~ral1l that ind icates the charge di stribution on the Gaussian cy li nders ' surfaces for a ll monomers

Conclusion (a) If the physicochemical parameter is -ve The fo rmati on of e ithe r continuous or discrete

resid ll a l charge types. on the heads and the ta il s' three

sec ti ons. o f mono me rs (a and c) and monomers (b

and d ), could cause cons tructi ve and des truct ive types of elec tron distribution over laps, respective ly. These overlaps are re presented in the fo llow ing Table VII.

No loc al electros tati c si tes are generated. So. one ca n deduce that the dipe ptide(s) inhibiti on inte rac ti on

ab ilities . to wards the me nti oned organi sm(s) . is inverse ly propo rti onal to the number of e lec tros ta ti c

si tes l') . There fore, the bi o logical inactive property is

domain. O ne ca n conc lude that the type of the charge on

secti on 2 . is thc onl y phys icochemical parame te r whic h co ntro ls the type o f the e lectron di stribution

ove rlap anci gene rat es loca l e lectrostatic s ites on the Gauss ian c ylindl'r surfaces.

(b) If the physicochemical parameter is +ve It could be speculated th at the formation of local

e lectrostatic si tes 0 11 the tai l's sec ti on of backbone and s ide chain res idues . cou ld cause local-stm cture-

1358 INDIAN J CHEM, SEC B, DECEMBER 1999

Table VII-Electron distribution overlaps

Ph ysi co­chemical parameter

Type of overlap

Monomers Real Charge di stribution Electron distribution

overlap biological Head Tail

status 2 3

+ve -ve -ve -ve

-ve Construct i ve a&c Inactive Continuous

+ No local electrostati c sites

+ve -ve +ve -ve

+ve Destructi ve b&d Active Discrete

di srupting of the covalency properties of the side chain bonds l9

. The process could separate a simple product, on which the organisms' growth might accelerate. Therefore, the biological active property is domain .

Finally, the type of the charges on section 2 of the Gaussian cylinder of the dipeptide tail , is the only physicochemical parameter suitable, to interpret the status of the biological ac tIvItIes of the four illtroduced dipeptide systems.

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