2007 International Conference on Convergence Information Technology
Computational Identification of Interaction Motifs in Hepatitis C Virus NS5A
and Human Proteins
Guang-Zheng Zhang Kyungsook Han∗
Biocomputing Lab., School of Computer Sciences & Engineering, Inha University
Incheon 402751, South Korea
aokunzhang@126.com khan@inha.ac.kr
Abstract
Identifying binding motifs or critical sequence segments
is a key step toward understanding the mechanism of in-
teractions between hepatitis C virus (HCV) and host cell
proteins, such as human proteins. In the present study, we
found a pair of binding motifs, G185 -L234 in HCV NS5A
proteins and L-X(3,5)-E-[AEGNQST] in human proteins,
which are considered to be a key determinant for the inter-
actions between HCV NS5A and human proteins. The bind-
ing motif of human proteins often forms a full helix (H) or an
extended strand-loop (EL) structure. We also found 3 highly
conserved sequence segments in HCV NS5A, G185 -D196 ,
R216 -L239 , and S414 -S437 , which are in good agreement with
the experimental results of previous studies. These results
are expected to prove helpful in the design of high-affinity
molecules that target the binding sites of HCV NS5A and
human proteins.
1. Introduction
Hepatitis C virus (HCV) encodes a polyprotein consist-
ing of core, envelope (E1, E2, and p7), and nonstructural
polypeptides (NS2, NS3, NS4A, NS4B, NS5A, and NS5B).
Though much effort has been directed toward the study of
the HCV folding and interaction mechanism, an effective
treatment for hepatitis C virus has not been found. The
study of HCV is very difficult because the virus does not
grow readily in tissue culture, and until very recently, there
has been no small animal model in which to propagate it
[1, 2]. Therefore, analysis of the interactions between HCV
and human proteins at the sequence or structure level would
present a significant step toward attaining a more complete
understanding of the interaction of HCV with host cells and
also guide experiments effectively.
∗ Correspondence: Kyungsook Han, Phone: +82 32 860 7388, Fax: +82
32 863 4386, E-mail: khan@inha.ac.kr
0-7695-3038-9/07 $25.00 © 2007 IEEE
DOI 10.1109/ICCIT.2007.67
HCV NS5A is a viral regulatory protein that modulates
viral RNA replication and host processes by interacting with
a variety of host regulatory factors [3, 4]. In the present
study, we analyze the interactions between HCV NS5A and
human proteins, and attempt to find functionally important
motifs and structure patterns in binding segments of both
NS5A and human proteins. To our knowledge, this is the
first attempt to find binding motifs both at the sequence and
structure levels for the interactions between HCV and hu-
man proteins. This could, to some degree, provide useful
guidelines for future experiment designs as well as insight
into HCV-human interaction mechanism.
2 Data Preparation
The Biomolecular Object Network Dadabank (BOND
[5]) provides a wealth of insight into interactions between
different types of proteins. As of January 8th, 2007, it
contains about 190,824 interactions in 3,705 protein com-
plexes. By setting the taxonomy IDs to 11103 (Hepc) and
9606 (Human), we searched for HCV-human interactions
in BOND, and obtained a total of 127 interactions between
HCV and human proteins (see the supplementary mate-
rial for details). Of these 127 interactions, there are 39
entries of HCV NS5A-human interactions, 24 entries of
HCV core-human interaction, and 15, 13, and 12 entries
for E2-, NS3-, and NS5B-human interaction, respectively.
Table 1 summarizes the interactions between NS5A viral
regulatory proteins and human proteins. As shown in Ta-
ble 1, a total of 5 HCV NS5A viral regulatory proteins
(NP 751927.1, CAB46677.1, AAB87527.1, NP 671491.1,
and AAQ86584.1) interact with human proteins. All the in-
teractions between these 5 HCV NS5As and human proteins
listed in this table are adopted to analyze potential interac-
tion motifs.
885
3 RESULTS AND DISCUSSION
3.1 Relation of HCV NS5A Protein Vari-
ants
As shown in Table 1, there are five HCV NS5A pro-
tein variants (CAB46677.1, NP 751927.1, AAB87527.1,
NP 671491.1, and AAQ86584.1), which interact with hu-
man proteins. Among the 5 NS5A proteins, NP 671491.1
is a whole HCV polyprotein of 3011 aa, and CAB46677.1
is HCV subtype 1b of 3010 aa. These two HCV pro-
teins show a high sequence similarity of 94.16% (86.12%
identity plus 8.04% strong similarity). This suggests that
the two proteins would show similar properties when in-
teracting with human proteins. The other two NS5A pro-
teins, AAQ86584.1 and AAB87527.1, are intercepted parts
of HCV genotype 1b [6]. These two proteins are vari-
ants of NP 751927.1 viral regulatory protein, and have
high sequence similarities of 96.06% and 94.04% with
NP 751927.1, respectively. Further, from Table 1, it can
be seen that NS5As NP 751927.1 and CAB46677.1 are the
most frequently involved in interactions with human pro-
teins. Specifically, CAB46677.1 has 19 interacting hu-
man proteins, whereas NP 751927.1 has 15 interacting
human proteins. The other three HCV NS5A proteins,
AAB87527.1, NP 671491.1, and AAQ86584.1, have only
2, 2, and 1 human counterparts, respectively. Hence,
NP 751927.1 was adopted as a representative protein of
these five variants.
3.2 Mapping of the Interacting HCV
NS5A Segments
To simplify the study of the interactions between HCV
NS5A and human proteins, we mapped all the interacting
segments of the five NS5A protein variants to NP 751927.1,
which is the representative protein of HCV NS5A pro-
tein variants. The two segments 1973-2272 and 2272-2419
of NS5A CAB46677.1, for example, share high sequence
identities of 95.11% and 96.35% with sequence segments
1-300 and 300-438 of NP 751927.1, respectively. This sug-
gests that the similar sequence segments may share similar
3D structures and functions, so we consider the sequence
segment 1-438 of NP 751927.1 as a substitute for the bind-
ing segment 1973-2419 of CAB46677.1 for further study.
Whereas, the other three sequence segments 1-173, 1-234,
and 277-447 of NP 751927.1 belong to the HCV E1 or E2
envelope protein variants. Hence, these 3 sequence seg-
ments were excluded from further study. In this manner,
we could map all interacting segments to NP 751927.1 vi-
ral regulatory protein (Table 2).
886
3.3 Conservation and Binding Motifs of
HCV NS5A Protein
Conservation of NS5A protein sequence segments was
computed at every position of the sequence using the def-
inition described in [7]. If sequence conservation > 3.5
in more than 85% positions of the sequence segment, we
consider the segment is highly conserved and functionally
important during evolution. A total of 3 highly conserved
sequence segments, G185 -D196 , R216 -L239 , and S414 -S437 ,
were identified by using multiple sequence alignments of
HCV proteins. The consensus sequences of these 3 con-
served segments are GSQLpCePEPD, RRLarGSpPSlAsS-
sasQLSapsl, and SSMPPLEGEPGDPDLsdgsWSTVS, re-
spectively. Moreover, the alignment of 5 NS5A viral reg-
ulatory proteins listed in Table 2 also indicate that these
3 segments are highly conserved. These highly conserved
segments may be functionally important for NS5A interact-
ing with human proteins.
By executing the program PRATT [8] with the multiple
sequence alignment of NS5A protein homologies as input,
we found the following sequence motif:
G-S-Q-L-[PS]-C-[DE]-P-E-P-D-X(1,2)-V-X(2,3)-S-M-L-
X-D-P-[ADPST]-H-[ILV]-T-[AV]-[AE]-[AEST]-A-X-R-
R-L-X-[KR]-G-S-X-P-S-X-A-[NS]-S-X-[AV]-[NS]-Q-L
This motif is located at G185 -L234 of the HCV NS5A
NP 751927.1 protein sequence, which includes 49 residues
and can be described as:
GSQLPCEPEPDvaVlt.SMLtDPSHITAEAAgRRLaRGSpP
SmASSsASQL
where a capital letter indicates that the position is
fully conserved, and a lowercase letter denotes that the
particular residue is predominant at that position. The
sequence logo and structure of this sequence motif are
illustrated in Figure 1. The highly conserved sequence
segments and sequence motif are in good agreement.
Of the three highly conserved segments, two segments
(G185 -D196 and R216 -L239 ) match perfectly the sequence
motif G185 -L234 . The other sequence segment S414 -S437 ,
according to an earlier report [3], lies in the segment of
aa 412-477, which is essential to NS5A binding ability.
Hence, it can be concluded that the three highly conserved
sequence segments are important for the interaction of
HCV NS5A with other proteins and that the sequence motif
plays an important role in the interaction of HCV NS5A
and human proteins.
The NS5A sequence motif identified in this study is also
consistent with the experimental results of previous stud-
ies [2, 9]. Evans et al. [2] reported that the sequence seg-

Figure 1. The sequence logo and secondary
structure of the segment 185-234 of NS5A
NP 751927.1. The sequence logo repre-
sents the residues by types: polar residues
in green, hydrophobic residues in orange,
acidic residues in red, and basic residues in
blue.
ment 2177-2228 of HCV polyprotein encodes NS5A de-
terminants for its interaction with hVAP-A human protein.
The segment of 2177-2228 can be mapped to the segment
of D205 -E256 of NS5A NP 751927.1, which has a substan-
tial overlap with the proposed sequence motif G185 -L234 .
Moreover, [9] reported that NS5A mutants including the
sequence segment E148 -E301 interact with human protein
TRAF2, but the mutant including S238 -C447 loses the abil-
ity to interact with TRAF2. This indicates that the NS5A se-
quence fragment E148 -S238 is critical for the NS5A-TRAF2
interaction. The sequence motif G185 -L234 found in our
study is also included in this region, this suggests that the
proposed motif is potentially valuable in designing future
experiments to identify critical residues or sites in the inter-
actions of HCV NS5A and human proteins.
3.4 Binding Segments of Human Proteins
Table 1 lists all the human proteins interacting with HCV
NS5A viral regulatory proteins. There are 32 human pro-
teins involved in the interactions with NS5A proteins. We
extracted human protein sequences from the BOND and
NCBI databases, and used the Sequence Homology Tool
of PubGene [10] to find homologous sequences of these 32
human proteins from PDB. Among the 32 human proteins,
only 12 proteins have their PDB counterparts as shown in
Table 3.
Consider the human protein (NCBI ID 21536411) as an
example. Its binding segment 393-482 has a high sequence
identity with the sequence segment 124-213 of the matched
protein (PDB ID 1MV3). This suggests that these two se-
quence segments may have a similar 3D structure. Hence,
we used the structure data of the matched protein (PDB
ID 1MV3) to study the interaction between NS5A and hu-
man protein with NCBI ID 21536411. In this manner, we
mapped all the binding segments of human proteins listed
887
in Table 1 to homologous proteins in PDB. Only 12 hu-
man proteins out of 32 have homologous human proteins
with known structures found in PDB. The remainder of this
paper discusses the interactions between the 12 human pro-
teins and HCV NS5A viral regulatory protein.
3.5 Binding Motif and Structure Pattern
of Human Proteins
The interacting segments of the 12 human proteins have
different sequence lengths, as shown in Table 3. The human
protein NCBI ID 20428652 has an interacting segment of 52
residues, whereas the human protein NCBI ID 8400738 has
an interacting segment of 240 residues. Due to the big dif-
ference in sequence lengths, multiple sequence alignment of
the 12 proteins is not a good way of finding sequence mo-
tifs. Hence, an online sequence motif search tool, PRATT
[8], was used to discover sequence motifs of the 12 human
proteins. A sequence motif, L-X(3,5)-E-[AEGNQST], was
thereupon found in the binding sites of the 12 human pro-
teins. This motif can be considered to be highly conserved
across long periods of human protein evolution, and be
functionally important for human proteins interacting with
the HCV NS5A protein.
The binding motif L-X(3,5)-E-[AEGNQST] occurs 23
times in the 12 human proteins, and forms one of the fol-
lowing secondary structure patterns: H{(7, 8}, E{7, 8},
L{(7, 8}, and E{2, 5}-L{2, 5}, where H, E, and L repre-
sent helix, extended strand, and loop, respectively. H{7, 8}
denotes a helix of 7 to 8 residues. The 4 structure patterns,
H{7, 8}, E{7, 8}, L{7, 8}, and E{2, 5}-L{2, 5}, occur 8, 5,
3, and 8 times, respectively, in the total 23 occurrences of
the binding motif. A full helix (i.e., H{7, 8}) and an ex-
tended strand followed by loop (i.e., E{2, 5}-L{2, 5}) are
the most frequent structure patterns formed by the binding
sites of human proteins interacting with the NS5A protein.
This structure information would be helpful to narrow the
search space of binding segments identification. Figure 2
gives the structure of the binding motifs of 6 human pro-
teins (PDB codes 2A01, 2CBR, 2FHA, 1YCS, 1W1F, and
1GRI).
3.6 Statistical Analysis of Binding Motifs
To determine the statistical significance of the bind-
ing motifs, we searched the motifs in a large set
of random sequences and compared the results. Us-
ing the random protein sequence generator of ExPASy
(http://www.expasy.org/tools/randseq.html), we generated a
total of 500 randomized protein sequences of equal length
as the HCV NS5A protein (428 aa). The average amino
acid composition in Swiss-Prot was retained in the random
sequences. There was only one occurrence of the motif in
the 500 random sequences. Hence, the probability of find-
ing the binding motif of HCV NS5A is as low as 0.002,
suggesting that the motif is hard to find by chance.
In the same way, we generated a new set of 500 random
sequences of equal length as the average human proteins
interacting with HCV NS5A (99 aa). We also predicted
secondary structures of the random sequences using GOR
[11]. In the 500 random sequences, there were 44 hits which
match the binding motif both in sequences and structure pat-
terns. Any of the 4 structure patterns, full helix (H), full
extended strand (E), full loop (L), and extended strand-loop
(EL), was allowed. Hence, the probability of finding the
binding motif of human proteins is as low as 0.096, again
suggesting that the motif is hard to find by chance.
We also attempted to find the proposed motif in
three human proteins, which were not included in the
initial 12 human proteins used for deriving the bind-
ing motif: NP 036289.2 (F-box and leucine-rich re-
peat protein 2), NP 002101.2 (tyrosine protein kinase
HCK), and NP 003185.1 (TATA box Binding Protein).
We found 4 occurrences of the motif in NP 036289.2
(L148 kgisEG154 , L262 qilEA267 , L288 ekmdlEE295 , and
L359 ehlEN364 ), and only one occurrence in the other hu-
man proteins each (L126 lrrEG131 in NP 002101.2 and
L49 sileEQ55 in NP 003185.1). All these motifs were found
within the binding segments of the human proteins. This
suggests that the proposed motif is in a good agreement with
the experimental data.
4 CONCLUSIONS
Based on the analysis of the interactions between HCV
NS5A and human proteins, we identified three highly
conserved sequence segments (G185 -D196 , R216 -L239 , and
S414 -S437 ) and one binding motif (G185 -L234 ) in HCV
NS5A protein with NCBI ID 26053629. In addition to
the conserved segments, a sequence motif L-X(3,5)-E-
[AEGNQST] and its structure were identified in the bind-
ing sites of human proteins. The binding sites of human
proteins often form a full helix (H) or an extended strand-
loop (EL) structure. Statistical analysis of the binding mo-
tifs, G185 -L234 in HCV NS5A proteins and L-X(3,5)-E-
[AEGNQST] in human proteins, shows that the binding mo-
tifs are statistically significant and hard to find by chance in
random sequences. The binding motif and its exact role
in the interactions between NS5A and human proteins re-
main to be verified by biochemical experiments. However,
the observations reported in this study should have valu-
able implications for the design of site-directed mutagenesis
experiments targeting HCV NS5A-human protein interac-
tions. In the future, we will expand this analysis method to
the interactions between other HCV nonstructural proteins
and human proteins.
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ACKNOWLEDGEMENTS
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government (KRF-
2006-D00038) and by KOSEF through the Systems Bio-
Dynamics Research Center.
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 Table 1. Interactions between HCV NS5A viral regulatory proteins and human proteins, extracted
from the BOND database
HCV NS5A proteins Human Proteins
NCBI Interacting NCBI Interacting
Interaction Descriptions Accession Segments GenInfo ID Segments
NS5A interacts with Grb2 CAB46677.1 277-447 4504111 –
NS5A interacts with Amph II2 CAB46677.1 – 21536411 393-482
NS5A interacts with Amph II2 short CAB46677.1 1-173 21536415 –
NS5A interacts with hVAP-A CAB46677.1 1-173 37588850 –
ApoE interacts with NS5A from HCV type 1b isolate Con1 CAB46677.1 – 4557325 –
NS5A interacts with FBL2 CAB46677.1 1-234 16306582 67-423
NS5A interacts with AHNAK CAB46677.1 – 535177 71-293
NS5A interacts with SFRP4 CAB46677.1 – 4506895 69-315
NS5A interacts with NDRG1 CAB46677.1 1973-2272 37655183 123-261
NS5A interacts with MGP CAB46677.1 1973-2272 13528966 1-103
NS5A interacts with CRABP-1 CAB46677.1 2272-2419 4758052 45-137
NS5A interacts with FTH1 heavy polypeptide 1 CAB46677.1 2272-2419 56682959 31-183
NS5A interacts with Translokin CAB46677.1 2272-2419 29469444 57-500
NS5A interacts with MGC2574 CAB46677.1 2272-2419 13129104 4-294
NS5A interacts with TACSTD2 CAB46677.1 2272-2419 14495611 –
NS5A interacts with Pl4K CAB46677.1 2272-2419 17105400 1799-1916
NS5A interacts with PTMA CAB46677.1 2272-2419 21359860 –
NS5A interacts with CENT-δ-2 CAB46677.1 2272-2419 16975484 850-1181
NS5A interacts with C9 ORF6 CAB46677.1 2272-2419 8923431 26-181
HCV NS5A interacts with apolipoprotein apoA1 NP 751927.1 – 4557321 1-167
HCV nonstructural 5A interacts with karyopherin beta 3 NP 751927.1 1973-2172 24797086 1007-1097
NS5A interacts with Hck NP 751927.1 – 30795229 82-135
NS5A interacts with Lck NP 751927.1 – 20428652 66-118
NS5A interacts with Lyn (Src-family protein tyrosine kinase) NP 751927.1 – 4505055 67-120
NS5A interacts with Fyn (Protein-tyrosine kinase fyn isoform) NP 751927.1 – 4503823 87-140
NS5A interacts with hVAP-33 NP 751927.1 – 37588850 156-242
NS5A interacts with SRCAP (Snf2-Related CBP Activator) NP 751927.1 – 5730067 –
NS5A interacts with p53 (Tumor protein p53) NP 751927.1 – 8400738 1-10 and 34-393
NS5A interacts with TRAF2 NP 751927.1 148-337 22027612 1-358
1-301 314-501
Human Vesicle-Associated Pro. (hVAP-33) interacts with NS5A NP 751927.1 – 36588850 1-48
p53 interacts with the Hepatitis C virus protein NS5A NP 751927.1 – 8400738 –
hTAFII32 interacts with the Hepatitis C virus protein NS5A NP 751927.1 – 4507351 1098-1620
NS5A interacts with Jak1 NP 751927.1 – 4504803 –
NS5A interacts with FBL2 NP 751927.1 – 16306582 –
NS5A interacts with La (autoimmune RNA-binding protein) NP 671491.1 1983-2025 10835067 –
1973-2050
Apolipoprotein E precursor (ApoE) interacts with NS5A NP 671491.1 1983-2025 4557325 314-501
NS5A interacts with TBP (TATA box Binding Protein) AAB87527.1 1-101 4507379 1-281
NS5A interacts with p53 (Tumor protein) AAB87527.1 – 8400738 –
Hepatitis C virus NS5A interacts with apolipoprotein apoA1 AAQ86584.1 1-224 4557321 1-167

889
 Table 2. Interacting segments of HCV NS5A proteins. The last column shows the interacting seg-
ments mapped to NS5A NP 751927.1.

NCBI Sequence Interacting Segments Mapping

Accessions Description length Segments to NP 751927.1
CAB46677.1 polyprotein [Hepatitis C virus subtype 1b] 3010 1-173, 1-234, 277-447 –
1973-2272 1-300
2272-2419 300-438
NP 751927.1 NS5A protein [Hepatitis C virus] 448 1-301, 148-337 1-301, 148-337
AAB87527.1 non-structural 5A protein [Hepatitis C virus] 452 1-101 1-99
NP 671491.1 polyprotein [Hepatitis C virus] 3011 1983-2025 1-53
1983-2029 10-57
1973-2050 1-78
AAQ86584.1 NS5A [Hepatitis C virus] 254 1-224 177-401

Table 3. Interacting segments of human proteins mapped to their PDB counterparts

BIND IDs of NCBI records of Human proteins Corresponding PDB records
Interactions between NCBI Sequence Experimentally determined PDB Sequence Mapped
NS5A & Human Proteins IDs Length binding segments IDs Length Segments
180343 21536411 482 393-482 1MV3 213 124-213
19203 / 24509 4557321 267 1-167 2A01 chain A 243 1-143
195937 4758052 137 45-137 2CBR 172 44-136
195938 56682959 183 31-183 2FHA 183 31-183
185259 37588850 242 156-242 2CR1 chain A 145 8-55
183543 22027612 501 314-501 1CA9 chain F 192 5-192
181843 / 130446 8400738 393 1-240 1YCS chain A 199 1-147
171699 4503823 537 87-140 1AVZ chain C 171 3-56
171698 4505055 512 67-120 1W1F chain C 65 9-62
171697 20428652 509 66-118 1KIK chain A 57 3-55
171696 30795229 526 82-135 1BU1 chain F 58 2-55
Sample et al
171700 4504111 217 – 1GRI chain B 217 1-217

(a) (b) (c)

(d) (e) (f)

Fig. 7. Diagram of sequence motif structure of human proteins (PDB code: 2A01, 2CBR, 2FHA, 1YCS, 1W1F, and 1GRI) interacting with NS5A.
Figure 2. Structure of binding motifs of 6 human proteins (PDB codes: 2A01, 2CBR, 2FHA, 1YCS,
1W1F, and et1GRI) interacting
al., 2006). with HCV
But the biggest stumbling NS5A
block in protein. R:L , and S:S ) and one sequence motif ( G-L )
HCV research 216 239 414 437 185 234
is the lack of a cell culture and small animal model for studying were identified within the primary sequence of NS5A with NCBI ID
viral replication and pathogenesis, which are expensive and time 26053629. These residue fragments may play a critical role for HCV
consuming. Hence, we focused on the residue information of NS5A interacting with other proteins or with other parts of HCV
interaction between HCV NS5A and human proteins and tried to protein. Whether or not these analysis and discussion accurately
identify functional important residue segments. This may provide us depict the interactions between NS5A and human proteins remains
much useful residue-level information to depict HCV-human protein to be verified by experiments. The observations presented in the
interaction, as well as guides for future experiment design. 890
present paper have potential implications for the design of site-
HCV NS5A is a viral regulatory protein that modulates viral RNA directed mutagenesis experiments targeting HCV NS5A-human
replication and host process by interacting directly and indirectly protein interactions. Next step, we will expand this analysis method
with a variety of host regulatory factors. The important role of NS5A to the interactions between other HCV nonstructural proteins and
in HCV RNA replication and its interaction with other proteins human complexes.
has been clearly demonstrated by high or clustered incidence of
adaptive systems, although the molecular mechanism involved